DDR
DRUG DEVELOPMENT RESEARCH 75 : S42–S45 (2014)
Clinical Overview
Use of Anti-Tumor Necrosis Factor Alpha Therapy in Patients with Concurrent Rheumatoid Arthritis and Hepatitis B or Hepatitis C: A Retrospective Analysis of 32 Patients Eleonora Ballanti, Paola Conigliaro, Maria Sole Chimenti,* Barbara Kroegler, Gioia Di Muzio, Maria Domenica Guarino, Paola Triggianese, Gianfranco Gigliucci, Lucia Novelli, Carmen Barbato, and Roberto Perricone Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi,” University of Rome Tor Vergata, Roma 00133, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re-activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease-modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti-TNF-α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients. Drug Dev Res 75 : S42–S45, 2014. © 2014 Wiley Periodicals, Inc. Key words: rheumatoid arthritis; anti-TNF; hepatitis B; hepatitis C
INTRODUCTION
The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of reactivation of HBV. This condition can occur in both inactive and occult carriers during immunosuppressive treatment [Lan et al., 2011]. Thus, we report our experience of using etanercept (ETA) and adalimumab (ADA) in patients with RA and previous HBV or HCV infection.
the 1987 revised criteria of the American College of Rheumatology (ACR) [Arnett et al., 1988] and received subcutaneous anti-TNF drugs ETA or ADA. All patients previously treated with disease-modifying
Funding/support information: The authors did not receive any funding for this work. Conflict of interest: E.B., P.C., B.K., G.D.M., M.D.G., P.T., G.G., L.N., C.B., R.P. have no conflicts of interest. M.S.C. has served as a consultant for Pfizer, Janssen Cilag, and MSD.
METHODS AND MATERIALS
*Correspondence to: Maria Sole Chimenti, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Viale Oxford 81, Roma 00133, Italy. E-mail: [email protected]
We performed a retrospective evaluation of the medical records of 344 patients with RA who fulfilled
Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21193
© 2014 Wiley Periodicals, Inc.
ANTI-TNF-Α IN RHEUMATOID ARTHRITIS AND HEPATITIS
anti-rheumatic drugs (DMARDs) including methotrexate had active disease (evaluated with the disease activity score on 28 joints [DAS28]), and so anti-TNF-α therapy was initiated. ETA was given at a dose of 50 mg weekly in 19 patients and ADA at a dose of 40 mg every other week in 13 patients, with or without DMARDs and corticosteroids. The scientific ethics committee of the University of Rome Tor Vergata approved the study and informed consent was obtained from each patient. All patients were assessed for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core (antiHBc), antibodies to HBsAg (anti-HBs), and antibodies to HCV (anti-HCV). Thirty-two patients were found to be positive for anti-HBcHbsAg, or anti-HCV. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and HBsAg were assessed every 3 months and HBV/HCV viral load was assessed every 6 months from initiation of anti-TNF-α therapy up to 6 years of follow-up. ALT and AST assays were performed by kinetic spectrophotometry. HBsAg, anti-HBc, and anti-HBs were determined by electrochemiluminescence immunoassay, and quantitative HBV/HCV viral loads by polymerase chain reaction (PCR; Dipartimento di Medicina di Laboratorio, University of Rome Tor Vergata). Patients were classified according to the following definitions: inactive HBsAg carriers (HBsAg+, HBV DNA 105 (>2.6 log)
S43
copies/mL or a 10-fold rise in HBV DNA [European Association for the Study of the Liver, 2009]. RESULTS
Among 344 RA patients evaluated for the presence of HBV and HCV serum markers, we found 32 relevant subjects (Table 1): 25 HBV occult carriers (7.3%, 24 positive for anti-HBc and anti-HBs, 1 positive for anti-HBc only), 1 HBV inactive carrier (0.2%), and 6 anti-HCV positive patients (1.7%). Three patients (the inactive carrier and two of the 25 occult carriers) received prophylactic treatment with lamivudine (100 mg/day) that was initiated 1 month before starting anti-TNF-α treatment and continued throughout the treatment period. We did not detect HBsAg development in the occult carriers; HBV DNA and HCV RNA were undetectable both at baseline and during the follow-up period in all patients. We did not observe any HBV or HCV reactivation nor it was necessary to stop biologic therapy because of viral infection. During the observation period, seven patients showed an increase in ALT and/or AST levels (Table 2): of these, three HBV occult carriers were treated with ETA (3/16,18.7%), three HBV occult carriers received ADA (3/10, 30%), and one HCV-positive patient received ETA (1/3, 33.3%). There was no significant difference in the percentage of patients with increased transaminase between the ETA and ADA groups (Fisher’s test, P = 0.6). The increase of transaminases was associated
TABLE 1. Characteristics of the 32 Enrolled Patients at Baseline Parameter N Age, years Gender (M/F) RA disease duration, years DAS28 DMARDs (n) Prednisone ≥7.5 mg/day (n) Anti-TNF duration, months HBsAg+ (n) Anti-HBs+ (n) Anti-HBc+ (n) HBV DNA level >2000 IU/mL Anti-HCV positive (n) HCV RNA level >12 copies/mL ALT (IU/L) (range)
Total
Etanercept
Adalimumab
32 63.26 ± 8.93 2/30 12.23 ± 5.78 5.17 ± 2.10 23 5 27.16 ± 23.66 1 24 25 0 6 0 24.26 ± 11.19(9–46)
19 63.74 ± 8.73 2/17 12.06 ± 6.39 5.14 ± 2.13 12 3 28.26 ± 26.12 1 14 15 0 3 0 21.35 ± 10.1 (9–44)
13 62.38 ± 9.19 0/13 12.5 ± 4.98 5.22 ± 2.2 11 2 26 ± 20.46 0 10 10 0 3 0 27.38 ± 11.81(13–46)
Data are mean ± standard deviation. ALT, alanine aminotransferase; anti-HBs, antibody to hepatitis B surface antigen; AST, aspartate aminotransferase; DAS28, disease activity score 28; DMARDs, disease-modifying anti-rheumatic drugs; HBc antibodies to hepatitis B core; HBsAg, hepatitis B virus surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; N, number; RA, rheumatoid arthritis; TNF, tumor necrosis factor.
Drug Dev. Res.
Drug Dev. Res.
No
F
10
60 10
75
Yes No
3
30/103
35/148
HBsAg-, HBcIgG+, anti-HBs+ Adalimumab No No
No
F
Patient 4
18
65
No No
3
36/127
45/199
HBsAg-, HBcIgG+, anti-HBs+ Adalimumab LEF No
No
F
Patient 5
12
57
14/35
22/98
Recurrent 3, 48, 60
No No
Yes, history of alcohol addiction HBsAg-, HBcIgG+, anti-HBs+ Etanercept HCQ No
M
Patient 6
HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA
DRUG DEVELOPMENT RESEARCH 75 : S42–S45 (2014)
Clinical Overview
Use of Anti-Tumor Necrosis Factor Alpha Therapy in Patients with Concurrent Rheumatoid Arthritis and Hepatitis B or Hepatitis C: A Retrospective Analysis of 32 Patients Eleonora Ballanti, Paola Conigliaro, Maria Sole Chimenti,* Barbara Kroegler, Gioia Di Muzio, Maria Domenica Guarino, Paola Triggianese, Gianfranco Gigliucci, Lucia Novelli, Carmen Barbato, and Roberto Perricone Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi,” University of Rome Tor Vergata, Roma 00133, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of hepatitis re-activation. This paper reports experience of using etanercept and adalimumab in 32 patients with RA and previous HBV or HCV infection. No cases of HBV or HCV reactivation were seen. In just over a fifth of patients, increased transaminases levels were seen, which were associated with concomitant use of disease-modifying antirheumatic drugs, isoniazid prophylaxis, or alcohol abuse. In our experience, anti-TNF-α therapy appears to be safe in RA patients with previous HBV or HCV infection, but monitoring remains necessary in these patients. Drug Dev Res 75 : S42–S45, 2014. © 2014 Wiley Periodicals, Inc. Key words: rheumatoid arthritis; anti-TNF; hepatitis B; hepatitis C
INTRODUCTION
The safety of tumor necrosis factor-alpha (TNF-α) inhibitors in the setting of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is controversial. The use of anti-TNF-α in rheumatoid arthritis (RA) is associated with an increased risk of reactivation of HBV. This condition can occur in both inactive and occult carriers during immunosuppressive treatment [Lan et al., 2011]. Thus, we report our experience of using etanercept (ETA) and adalimumab (ADA) in patients with RA and previous HBV or HCV infection.
the 1987 revised criteria of the American College of Rheumatology (ACR) [Arnett et al., 1988] and received subcutaneous anti-TNF drugs ETA or ADA. All patients previously treated with disease-modifying
Funding/support information: The authors did not receive any funding for this work. Conflict of interest: E.B., P.C., B.K., G.D.M., M.D.G., P.T., G.G., L.N., C.B., R.P. have no conflicts of interest. M.S.C. has served as a consultant for Pfizer, Janssen Cilag, and MSD.
METHODS AND MATERIALS
*Correspondence to: Maria Sole Chimenti, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Viale Oxford 81, Roma 00133, Italy. E-mail: [email protected]
We performed a retrospective evaluation of the medical records of 344 patients with RA who fulfilled
Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21193
© 2014 Wiley Periodicals, Inc.
ANTI-TNF-Α IN RHEUMATOID ARTHRITIS AND HEPATITIS
anti-rheumatic drugs (DMARDs) including methotrexate had active disease (evaluated with the disease activity score on 28 joints [DAS28]), and so anti-TNF-α therapy was initiated. ETA was given at a dose of 50 mg weekly in 19 patients and ADA at a dose of 40 mg every other week in 13 patients, with or without DMARDs and corticosteroids. The scientific ethics committee of the University of Rome Tor Vergata approved the study and informed consent was obtained from each patient. All patients were assessed for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core (antiHBc), antibodies to HBsAg (anti-HBs), and antibodies to HCV (anti-HCV). Thirty-two patients were found to be positive for anti-HBcHbsAg, or anti-HCV. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and HBsAg were assessed every 3 months and HBV/HCV viral load was assessed every 6 months from initiation of anti-TNF-α therapy up to 6 years of follow-up. ALT and AST assays were performed by kinetic spectrophotometry. HBsAg, anti-HBc, and anti-HBs were determined by electrochemiluminescence immunoassay, and quantitative HBV/HCV viral loads by polymerase chain reaction (PCR; Dipartimento di Medicina di Laboratorio, University of Rome Tor Vergata). Patients were classified according to the following definitions: inactive HBsAg carriers (HBsAg+, HBV DNA 105 (>2.6 log)
S43
copies/mL or a 10-fold rise in HBV DNA [European Association for the Study of the Liver, 2009]. RESULTS
Among 344 RA patients evaluated for the presence of HBV and HCV serum markers, we found 32 relevant subjects (Table 1): 25 HBV occult carriers (7.3%, 24 positive for anti-HBc and anti-HBs, 1 positive for anti-HBc only), 1 HBV inactive carrier (0.2%), and 6 anti-HCV positive patients (1.7%). Three patients (the inactive carrier and two of the 25 occult carriers) received prophylactic treatment with lamivudine (100 mg/day) that was initiated 1 month before starting anti-TNF-α treatment and continued throughout the treatment period. We did not detect HBsAg development in the occult carriers; HBV DNA and HCV RNA were undetectable both at baseline and during the follow-up period in all patients. We did not observe any HBV or HCV reactivation nor it was necessary to stop biologic therapy because of viral infection. During the observation period, seven patients showed an increase in ALT and/or AST levels (Table 2): of these, three HBV occult carriers were treated with ETA (3/16,18.7%), three HBV occult carriers received ADA (3/10, 30%), and one HCV-positive patient received ETA (1/3, 33.3%). There was no significant difference in the percentage of patients with increased transaminase between the ETA and ADA groups (Fisher’s test, P = 0.6). The increase of transaminases was associated
TABLE 1. Characteristics of the 32 Enrolled Patients at Baseline Parameter N Age, years Gender (M/F) RA disease duration, years DAS28 DMARDs (n) Prednisone ≥7.5 mg/day (n) Anti-TNF duration, months HBsAg+ (n) Anti-HBs+ (n) Anti-HBc+ (n) HBV DNA level >2000 IU/mL Anti-HCV positive (n) HCV RNA level >12 copies/mL ALT (IU/L) (range)
Total
Etanercept
Adalimumab
32 63.26 ± 8.93 2/30 12.23 ± 5.78 5.17 ± 2.10 23 5 27.16 ± 23.66 1 24 25 0 6 0 24.26 ± 11.19(9–46)
19 63.74 ± 8.73 2/17 12.06 ± 6.39 5.14 ± 2.13 12 3 28.26 ± 26.12 1 14 15 0 3 0 21.35 ± 10.1 (9–44)
13 62.38 ± 9.19 0/13 12.5 ± 4.98 5.22 ± 2.2 11 2 26 ± 20.46 0 10 10 0 3 0 27.38 ± 11.81(13–46)
Data are mean ± standard deviation. ALT, alanine aminotransferase; anti-HBs, antibody to hepatitis B surface antigen; AST, aspartate aminotransferase; DAS28, disease activity score 28; DMARDs, disease-modifying anti-rheumatic drugs; HBc antibodies to hepatitis B core; HBsAg, hepatitis B virus surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; N, number; RA, rheumatoid arthritis; TNF, tumor necrosis factor.
Drug Dev. Res.
Drug Dev. Res.
No
F
10
60 10
75
Yes No
3
30/103
35/148
HBsAg-, HBcIgG+, anti-HBs+ Adalimumab No No
No
F
Patient 4
18
65
No No
3
36/127
45/199
HBsAg-, HBcIgG+, anti-HBs+ Adalimumab LEF No
No
F
Patient 5
12
57
14/35
22/98
Recurrent 3, 48, 60
No No
Yes, history of alcohol addiction HBsAg-, HBcIgG+, anti-HBs+ Etanercept HCQ No
M
Patient 6
HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA HBsAg-, HBV DNA
