ORIGINAL ARTICLE

The long-term effects of anti-TNF-a agents on patients withchronic viral hepatitis C and B infections

Tuncer TEMEL,1 D€ond€u €Usk€udar CANSU,2 Cengiz KORKMAZ,2 Timuc�in KAS�IFO�GLU2 and

Ays�eg€ul €OZAKYOL1

Divisions of 1Gastroenterology, and 2Rheumotology, Faculty of Medicine, Department of Internal Medicine, Eskis�ehir OsmangaziUniversity, Eskisehir, Turkey

AbstractAim: To evaluate the long-term effects of anti-tumor necrosis factor-alpha (TNF-a) therapy on patients with

chronic hepatitis B and C infections.

Methods: Rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease patients administered anti-TNF-atherapy for at least 36 months were retrospectively reviewed for hepatitis B or C serology, liver function tests,

viral load, genotype and liver biopsy results, if performed. Nine relevant cases receiving anti-TNF-a were evalu-

ated: six patients had chronic hepatitis C, one had chronic dual hepatitis B and C and two had chronic hepatitis

B infection.

Results: The patient with dual infection exhibited virologic breakthrough for hepatitis C and required treatment.

Two patients with occult hepatitis B infection developed hepatitis B surface antigen (HBsAg) reversion and low-

level viremia at the end of the study.

Conclusion: Long-term use of anti-TNF-a treatments may result in viral replication that requires anti-viral ther-

apy. Before determining the safety of anti-TNF drugs in the treatment of autoimmune diseases in patients with

hepatitis C infection, studies with large homogeneous patient groups must be performed, and the exact group of

hepatitis C virus infected patients for whom anti-TNF treatment would be deemed safe should be identified.

Prior to anti-TNF-a treatment, it seems logical to screen all patients for HBsAg and anti-HB core immunoglobu-

lin G status, especially in endemic regions. These patients must be followed periodically by means of alanine

aminotransferase, HBsAg and hepatitis B virus DNA to identify HBsAg reversion and active viral replication that

might require anti-viral prophylaxis or treatment.

Key words: anti-TNF-a treatment, autoimmune disease, chronic viral hepatitis.

INTRODUCTION

Tumor necrosis factor alpha (TNF-a) is a mediator of

inflammation and cellular immune responses. Elevated

TNF-a levels have been reported in patients with hepati-

tis C virus (HCV) and are associated with poor progno-

sis.1,2 Elevated TNF-a levels are also observed in the

serum and hepatocytes of patients with chronic hepati-

tis B virus (HBV). Unlike HCV, the use of TNF-a in HBV

patients may have a part in clearing and controlling

HBV by synergizing with interferon to suppress viral

replication; therefore, TNF-a inactivation could theoret-

ically lead to enhanced viral replication, thus reactivat-

ing or worsening the disease.3,4 Several case reports and

studies with small samples of rheumatologic and gas-

troenterological patients suffering from chronic hepati-

tis examined the safety and efficacy of anti-TNF-atherapy. These studies have reported that while anti-

TNF-a therapy is considered to be safe for HCV, it may

Correspondence: Dr Tuncer Temel, Division of Gastroenterol-ogy, Department of Internal Medicine, Faculty of Medicine,Eskis�ehir Osmangazi University, 26480 Eskisehir, Turkey.Email: ttemel@ogu.edu.tr

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

International Journal of Rheumatic Diseases 2014

result in viral reactivation in chronic HBV patients.5–8

Although we already know the short-term effects of

anti-TNF-a treatment in patients with HBV or HCV, we

still lack sufficient information about its long-term

effects. The present study aims to report the long-term

effects of treatment with TNF-a blockers in patients

with viral hepatitis exposure.

PATIENTS AND METHODS

Four rheumatoid arthritis (RA) and two Crohn’s disease

patients with hepatitis C, one RA patient with dual hep-

atitis B and C, one ankylosing spondylitis (AS) and one

Crohn’s disease patient with hepatitis B infection who

have been on TNF-a blocker treatment for at least

36 months were selected for evaluation. Characteristics

of the patients, disease durations, treatment details,

serum transaminases, viral loads and, if performed,

liver biopsy results were retrospectively reviewed.

Patients with HBV exposure received neither prophylac-

tic nor therapeutic treatments. A positive anti-HB core

(anti HBc) immunoglobulin G (IgG) result was the

only serologic marker of HBV exposure. In the case of

uncontrolled autoimmune diseases, patients with HCV

exposure did not receive therapeutic treatments. After

DNA extraction using a Qiagen kit (Hilden, Germany),

the presence of HBV DNA was determined by real-time

polymerase chain reaction (PCR; Arthus, Corbett

Research, Sydney, NSW, Australia). After RNA extrac-

tion using an Abbott kit (North Chicago, Illinois, USA),

the presence of HCV RNA was determined by real-time

PCR (Arthus, Corbett Research). A liver biopsy was per-

formed in one of the patients before and after the anti

TNF-a treatment given a high viral load at the begin-

ning of the study and an increase at viral load and

decompensation of the liver disease at the end of the

study. Pathological specimens were examined by the

same expert, and the results were defined according to

Knodell’s classification.

RESULTS

Nine patients were identified and included in the study;

of these patients, six displayed rheumatic autoimmune

disease and three had gastroenterological autoimmune

disease (six females and three males; mean age

52.2 years [range 41–65 years]; mean autoimmune

disease duration 6.7 years [range 4–10 years]) with

concomitant HCV and/or HBV infection. All patients

did not exhibit other concomitant co-morbidities or

infectious diseases and were naive for previous anti-

TNF-a therapy. Five patients were subcutaneously

administered 50 mg etanercept once a week for a mean

of 54.4 months (range 36–65 months). One patient

was subcutaneously administered 50 mg etanercept

once a week for 38 months followed by 5 mg/kg inflix-

imab at 8-week intervals for 24 months. Three patients

were on infliximab remission induction treatment

followed by 5 mg/kg infliximab maintenance therapy

at 8-week intervals for a mean of 38.7 months (range

36–41 months).

Prior to the therapy, HBV DNA results were negative,

and positive anti-HBc IgG results were the only sero-

logic marker for patients with sole hepatitis B exposure.

HBV DNA tests were positive with low-level viremia at

the end of the treatment in both of the patients with

sole hepatitis B exposure. HBsAg reappearance was

identified in patients with HBV breakthrough. While

aminotransferase levels were within normal range in

one of the patients with HBV breakthrough, amino-

transferase levels were slightly increased in the other

patient but not two-fold beyond the upper normal

limit.

Prior to the study, HCV RNA results were negative in

five of the six patients with sole hepatitis C exposure,

and HCV RNA levels were below the cut-off established

for low-level viremia (800 000 IU/mL) in patients with

positive HCV RNA results. While virologic break-

through was detected in one of the patients with a nega-

tive HCV RNA result prior to anti-TNF-a treatment and

low level viremia at the end of study, decreased viral

load was reported in one of the patients who displayed

low-level viremia prior to anti-TNF-a treatment. Amino-

transferase levels of the patients with hepatitis C expo-

sure were within normal range for the duration of the

study. All patients with a positive HCV RNA test result

prior to or at the end of the study were infected with

HCV genotype 1.

One patient had dual HCV/HBV infection with sero-

logical markers as HBsAg (�)/anti-HBs (�)/anti-HBc

IgG (+)/anti-HCV (+). Prior to and at the end of the

study HBV DNA results were negative. HBsAg reappear-

ance did not occur. The patient with dual HCV/HBV

infection exhibited low-level viremia prior to anti-TNF-

a treatment and high-level viremia at the end of the

study. With the exception of the patient with dual HCV/

HBV infection, no clinical or laboratory signs of decom-

pensation were noted throughout the entire study. A

liver biopsy specimen of the patient with dual HCV/

HBV infection indicated a four-point increase in the his-

tological activation index and a three-point increase in

fibrosis (Ishak scoring system) at the end of the study.

2 International Journal of Rheumatic Diseases 2014

T. Temel et al.

Patient characteristics and levels of liver

aminotransferase, serological markers, viral loads before

and after anti-TNF-a treatment are specified in Table 1.

DISCUSSION

TNF-a is an essential cytokine for a host’s defense

against infective pathogens, and it plays an essential

role in the control of viral infection and immune

response by recruiting and activating macrophages, nat-

ural killer cells, T cells and antigen-presenting cells.

High levels of TNF-a are associated with poor prognosis

and low response rates to interferon therapy in patients

with hepatitis C.9 In a phase II randomized double-

blind placebo controlled study by Zein et al., etanercept

was administered as an adjuvant treatment prior to

interferon-a 2b and ribavirin administration in treat-

ment-naive patients with chronic hepatitis C. In this

study, etanercept did not exhibit serious toxic effects in

HCV-infected patients and was identified as a safe adju-

vant therapy option.10 Numerous case reports indicate

that anti-TNF-a therapy in the setting of HCV appears

to be safe.11,12 However, the long-term effect of anti-

TNF-a agents on HCV is not clear. Parke et al. retrospec-

tively reviewed five RA patients with an established

HCV infection requiring anti-TNF-a therapy; anti-TNF-atherapy was administered to two of the five patients for

29 and 49 months; the liver function or virologic status

did not worsen in these patients. They concluded that

anti-TNF-a therapy is well tolerated without apparent

influence on the underlying HCV infection and appears

to be safe.12 Roux et al.13 also retrospectively reviewed

six patients: two RA patients with chronic hepatitis B

infection, one spondyloarthropathy case with chronic

hepatitis B infection and three RA patients with chronic

hepatitis C infection. Of these three patients with HCV,

two were treated with anti-TNF-a for 29 and

39 months, and viral reactivation was not observed. In

our study, viral replication remained stable in four of

the seven patients with HCV. A slight decrease in the

viral replication rate was noted in one of the patients.

The HCV RNA status of one patient became positive:

low-level viremia without clinical significance. Further,

HBV DNA was negative throughout the entire study;

the patient with dual HCV–HBV infections displayed a

high level of HCV replication that required antiviral

therapy. We must bear in mind that the case with high-

level viremia and decompensation at the end of

the study suffered from dual infections (HCV–HBV).

As previously reported, a more rapid progression to cir-

rhosis tends to occur in cases with dual HCV/HBV

infections compared with cases in which infections

occur separately.14 It has long been known that concur-

rence of viruses results in reciprocal inhibition for either

virus involved.15 Bellecave et al.16 reported that mutual

inhibition may result from indirect mechanisms medi-

ated by innate and/or adaptive host immune responses

rather than a direct virus-based mechanism. In a recent

review of anti-TNF-a treatment in patients with HBV

and HCV, it is assumed that anti-TNF drugs display a

safe profile despite reported heterogeneity and a rela-

tively short treatment period and follow-up time.17

False-positive anti-HCV test results in patients with

hyperglobulinemic states reportedly occur in approxi-

mately 23%, and 15% of patients with positive anti-HCV

results display spontaneous viral clearance. In our study

and review articles, most of the patients were diagnosed

with chronic HCV exclusively using a positive anti-HCV

test result. Liver biopsy, the standard evaluation

method for the assessment of grading and staging of

liver disease, was not performed in most of the cases. In

addition, patient groups are heterogeneous with various

genotypes and different basal levels of viremia and

co-morbid factors and co-morbid infections. Based

upon these data, it is difficult to contend that TNF-ablocker treatment is a safe option for patients with HCV

exposure, at least in long-term treatment schemes. We

hypothesize that the long-term use of TNF-a blockers

might have a role in increasing viral replication by indi-

rectly affecting innate and/or adaptive host immune

responses. In addition, antiviral therapy for HCV infec-

tion is an interferon-based regimen with a treatment

duration of 48 weeks for HCV genotypes 1–4 and

24 weeks for HCV genotypes 2, 3, 5 and 6 and inter-

feron-based treatment regimens are contraindicated for

patients with uncontrolled autoimmune diseases.18,19

Before determining the safety of anti-TNF drugs in the

treatment of autoimmune diseases in patients with

HCV infection, studies using large patient groups that

are homogeneous for genotype of the infection, viremia

levels, pathological stages/grades and co-morbidities

must be performed. In addition the exact group of

HCV-infected patients for whom anti-TNF treatment

would be deemed safe should be identified. Identifica-

tion of the exact safe group will also protect patients

from anti-TNF treatment-induced virologic break-

through and clinical deterioration, for which the only

treatment option (interferon-based regimens) is contra-

indicated.

The long-term safety and efficacy of anti-TNF-aagents in patients with chronic viral hepatitis B are

not clear. Reactivation of HBV infection is possible.

International Journal of Rheumatic Diseases 2014 3

Anti-TNF-a agents in chronic viral hepatitis

Table

1Patientch

aracteristicsan

dlevelofliveram

inotran

sferases,serologicalmarkers,viralload

sbefore

andafteran

ti-TNF-atreatm

ent

Patient1

Patient2

Patient3

Patient4

Patient5

Patient6

Patient7

Patient8

Patient9

Age,years/sex

58/F

65/F

61/F

51/F

41/F

60/M

56/M

44/M

34/F

Disease

RA

RA

RA

RA

AS

RA

CD

CD

CD

Viral

disease

HCV

HCV

HCV

HCV+HBV

HBV

HCV

HCV

HCV

HBV

Anti-TNF-aagen

tETN

ETN

ETN/INF

ETN

ETN

ETN

INF

INF

INF

Durationofan

ti-TNF-a

treatm

ent,months

63

65

38/24(62)

55

53

36

36

41

39

Viral

load

(IU/m

L)

Baseline

Negative

Negative

Negative

131023/–†

Negative

337680

Negative

Negative

Negative

Endoffollow-up

Negative

129,335

Negative

2535000/–†

24542

227367

Negative

Negative

24813

AST(IU/m

L)

Baseline

26

41

14

30

21

42

37

13

24

Duringfollow-up,med

ian(ran

ge)

19(10–2

8)

48(38–6

6)

30(13–6

6)

38(33–5

4)

16(12–3

4)

33(30–3

7)

31(22–4

9)

17(12–3

3)

34(26–7

8)

Endoffollow-up

20

45

23

33

20

37

ALT(IU/m

L)

Baseline

20

50

15

25

25

35

34

22

19

Duringfollow-up,med

ian(ran

ge)

17(13–2

1)

48(29–8

3)

31(14–7

3)

34(22–4

5)

17(11–2

1)

25(13–3

3)

16(12–2

3)

37(25–4

9)

40(31–7

1)

Endoffollow-up

14

40

21

34

14

13

33

38

67

HBsA

g

Baseline

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Endoffollow-up

Negative

Negative

Negative

Negative

Positive

Negative

Negative

Negative

Positive

Anti-H

Bs

Baseline

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Endoffollow-up

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Negative

Anti-H

BcIgG

Baseline

Negative

Negative

Negative

Positive

Positive

Negative

Negative

Negative

Positive

Endoffollow-up

Negative

Negative

Negative

Positive

Positive

Negative

Negative

Negative

Positive

Anti-H

CV

Baseline

Positive

Positive

Positive

Positive

Negative

Positive

Positive

Positive

Negative

Endoffollow-up

Positive

Positive

Positive

Positive

Negative

Positive

Positive

Positive

Negative

Biopsy

score

HAI/Stage

Baseline

7/2

Endoffollow-up

13/5

†Secondlevelsshow

HBVviralload

.ALT,alan

ineam

inotran

sferase;

AS,

ankylosingspondylitis;AST

,aspartate

aminotran

sferase;

CD,crohn’sdisease;ETN,etan

ercept;HAI,hep

aticactivity

index;HBV,hep

atitisBvirus;HCV,hep

atitisCvirus;IN

F,inflixim

ab;RA,rheu

matoid

arthritis;TNF,

tumornecrosisfactor.

4 International Journal of Rheumatic Diseases 2014

T. Temel et al.

Several case reports that emphasize the effect of anti-

TNF-a agents on chronic HBV infection have been

published. Zingarelli et al.5 reported on three patients

with positive HBsAg test results, treated with anti-

TNF-a agents under lamivudine (LAM) prophylaxis.

These three cases used anti-TNF-a agents for 36, 48

and 12 months. Reactivation with prolonged LAM

therapy after cessation of anti-TNF-a agents was not

observed. Sakellariou et al. reported two AS cases with

HBV, and HBV reactivation was observed in one of

the patients at the 14th week. After initiation of

antiviral therapy with LAM, viral load and transami-

nase levels returned to negative and normal levels,

respectively.20 Currently, treatment or prophylaxis

schemes have been utilized in patients with HBV

exposure who plan to receive immunosuppressive

therapy.21,22 Long-term antiviral prophylaxis and/or

therapy with nucleoside/nucleotide anti-viral agents in

patients receiving long-term anti-TNF-a agents is safe

and effective for chronic active viral hepatitis B or

chronic inactive hepatitis B infections.23,24 Although

outcomes with nucleoside/nucleotide anti-viral agent

prophylaxis and/or treatment in patients with chronic

active viral hepatitis B or chronic inactive hepatitis B

infections resuming immunosuppressive therapy are

satisfactory, conflicting data regarding occult viral

hepatitis B infection are present in the literature. In

one report, patients displayed a higher incidence of

reactivation in 88 occult carriers treated with etaner-

cept, infliximab or adalimumab. In contrast, two

additional reports indicated that reactivation rates

were low in occult carriers.25–27 Contradictory reports

seem to result from heterogeneous patient groups

with occult viral infection. All patients with a serolog-

ical result of HBsAg (�), anti-HBc IgG (+) and anti-

HBs Ab (�) were included into the study. In our

study, two of the three patients with occult viral hep-

atitis B infection (HBsAg [�], anti-HBc IgG [+], and

anti-HBs Ab [�]) displayed HBsAg reversion and low-

level viremia with normal or mild levels of amin-

otransferases. The third case had dual HBV–HCV

infection, and activation of HBV might be suppressed

by HCV. Reactivation rates were also higher in reports

of patients with a serology that mimics our patients.

In this way, prior to anti-TNF-a treatment, it seems

logical to screen all patients prior to anti-TNF-a treat-

ment for HBsAg and anti-HBc IgG status, especially at

endemic regions. In addition, these patients must be

followed periodically by means of alanine amino-

transferase, HBsAg and HBV DNA to assess HBsAg

reversion and active viral replication, which might

require anti-viral prophylaxis or treatment. We consid-

ered the dilemma regarding the anti-TNF-a treatment

upon hepatitis B exposure occurring in patients with

occult infection (represented as a serology of HBsAg

[�]/anti-HBs [�]/anti-HBc IgG [+]). The need for

HBV vaccination prior to immunosuppressive treat-

ment or prophylaxis schemes must be determined by

data obtained from studies with large patient groups

consisting of occult HBV patients receiving anti-TNF-atreatment.

AUTHOR CONTRIBUTIONS

Tuncer Temel and D€ond€u €Usk€udar Cansu designed the

study and directed its implementation, including qual-

ity assurance and control, Timuc�in Kas�ifo�glu helped

supervise the field activities, Tuncer Temel, D€ond€u€Usk€udar Cansu, Cengiz Korkmaz, Timuc�in Kas�ifo�gluand Ays�eg€ul €Ozakyol conducted the literature review

and prepared the Methods and the Discussion sections

of the text.

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