Rheumatol Int (2009) 29:777–780 DOI 10.1007/s00296-008-0790-6
O R I G I N A L A R T I CL E
Prophylactic use of lamivudine with chronic immunosuppressive therapy for rheumatologic disorders Umut Kalyoncu · Ozlem Yonem · Meral Calguneri · Osman Ersoy · Omer Karadag · Ali Akdogan · Sule A Bilgen · Sedat Kiraz · Ihsan Ertenli · Yusuf Bayraktar
Received: 15 June 2008 / Accepted: 24 September 2008 / Published online: 27 November 2008 © Springer-Verlag 2008
Abstract The objective of this study was to report our experience concerning the eVectiveness of the prophylactic administration of lamivudine in hepatitis B virus surface antigen (HBs Ag) positive patients with rheumatologic disease. From June 2004 to October 2006, 11 HBs Ag positive patients with rheumatologic diseases, who were on both immunosuppressive and prophylactic lamivudine therapies, were retrospectively assessed. Liver function tests, hepatitis B virus (HBV) serologic markers, and HBV DNA levels of the patients during follow-up were obtained from hospital Wle records. Eleven patients (six male) with median age 47 years (range 27–73), median disease duration 50 months (range 9–178) and median follow-up period of patients 13.8 months (range 5–27) were enrolled in this study. Lamivudine therapy was started 3–7 days prior to immunosuppressive therapy in all patients. Baseline, liver function tests were elevated in two patients (fourth patient: ALT:122 IU/l, AST:111 IU/l, tenth patient:ALT:294 IU/l, AST:274 IU/l, with minimal changes in the liver biopsy in both). Shortly after treatment their tests normalized and during follow-up period none of the patients had abnormal liver function tests. In four patients HBV DNA levels were higher than normal at baseline. Two of these normalized and the others increased later. In three additional patients, HBV DNA levels were increased during follow-up. None of the patients had signiWcant clinical sings of HBV activation. Lamivudine was well tolerated and was continued in all patients. Prophylactic administration of lamivudine in patients who required immunosuppressive therapy seems to
U. Kalyoncu (&) · O. Yonem · M. Calguneri · O. Ersoy · O. Karadag · A. Akdogan · S. A Bilgen · S. Kiraz · I. Ertenli · Y. Bayraktar Hacettepe University, Ankara, Turkey e-mail:
[email protected]
be safe, well tolerated and eVective in preventing HBV reactivation. Keywords Hepatitis B · Lamivudine · Immunosuppressive therapy
Introduction More than 300 million people worldwide suVer from persistent hepatitis B virus (HBV) infection, making the virus a common cause of morbidity and mortality. The prevalence of hepatitis B surface antigen (HbsAg) carriers ranges from 0.5 to 10%. HBV is endemic in Turkey and the seroprevalence of HBsAg ranges from 6.2 to 8.2% [1]. Exacerbation of HBV can be quite severe, leading to fulminant hepatitis and even death. Viral reactivation in HBV carriers undergoing immunosuppressive therapy ranges from 14 to 50%, associated with 5–12% mortality [2]. The reactivation of HBV infection has been reported to occur mainly following cessation of immunosuppressive treatment, but it can also occur during treatment. There are at least seven reports in the literature depicting HBV reactivation under immunosuppressive therapy in rheumatological disorders. In Wve of these seven reports, HBV reactivation was seen after decrease or interruption of the immunosuppressive regimen, while in two reports it was noted during chronic therapy [3]. Lamivudine is a reverse transcriptase inhibitor initially approved for antiviral therapy in human immunodeWciency virus (HIV) infection. It eVectively suppresses serum HBV DNA values in up to 98% of treated patients within a median period of 4 weeks and leads to aminotransferase normalization, increased HBV e antigen (Hbe) seroconversion rate and improvement of histological parameters [4].
123
778
In this study, we report our experience concerning the eVectiveness of the prophylactic administration of lamivudine in 11 HBV positive patients with rheumatologic diseases.
Materials and methods From June 2004 to October 2006, 11 HbsAg-positive patients who were candidates for immunosuppressive therapy for rheumatologic diseases were prescribed lamivudine prophylactic therapy. We retrospectively assessed and reviewed the medical records of each patient. Patients were treated with lamivudine at a dose of 100 mg/day as soon as possible prior to initiation of immunosuppressive therapy. Before the administration of lamivudine, the following examinations were performed: a.
Liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin levels were evaluated. These tests were measured by standard laboratory methods and performed during the follow-up period at monthly intervals. b. Serological tests related with HBV virus including HbsAg, antibody against HBV surface antigen (antiHBs), HBV antigen e (HBeAg), antibody against HbeAg (anti-HBe), and antibody against HBc (antiHBc) were measured by ELISA technique. HBV viral load was measured using polymerase chain reaction (Cobas amplications, Roche diagnosis). c. Abdominal ultrasonography was performed in all cases and liver biopsy in only three cases.
Results Eleven patients were included in the study, and their characteristics are shown in Table 1. Six patients were males; median age was 47 years (range 27–73). Median disease duration was 50 months (range 9–178) and median followup period of patients was 13.8 months (range 5–27). The underlying rheumatologic condition was rheumatoid arthritis (RA, n = 3); ankylosing spondylitis (AS, n = 3), systemic lupus erythematosus (SLE, n = 2), Henoch-Schonlein purpura (HSP, n = 1), Takayasu arteritis (TA, n = 1), and polymyositis (PM, n = 1). Except for patients number 4 and 10, all patients’ liver functions at baseline were normal (for patients 4 and 10, ALT/AST levels were 122/111 and 294/ 274 IU/ml, respectively). There was also no increase in transaminase levels during follow-up. All patients were HbsAg positive and only one patient had HbeAg positivity
123
Rheumatol Int (2009) 29:777–780
(Table 1). Anti-HBc was studied in 8 of the 11 patients and 7 of these 8 patients were found to be anti-HBc positive. Patient number 4 had anti-HCV (+) without detectable HCV RNA. Fatty liver was detected by abdominal ultrasonography in four patients and the others’ abdominal ultrasonographies were normal. At baseline, only mild hepatitis was found in liver biopsies of Wrst, fourth and Wfth patient. Patient’s baseline and follow-up HBV DNA value are shown in Table 1. Four patients’ HBV DNA values were higher than normal (regarding patient number 2, the level was >1,000 IU/ml) at baseline and three patients’ HBV DNA values were increased (the Wrst patient’s at baseline was 0 IU/ml and 15 months later 352 IU/ml, that of patient number 3 at baseline 0 IU/ml and 14 months later 992 IU/ ml, that of the seventh patient at baseline 27 IU/ml and 10 months later 3670 IU/ml) during follow-up. All patients’ treatment regimens are shown in Table 1. High dose corticosteroids were given to Wve patients and median total steroid dose was 11.7 g (range, 4.5–20 g) and all these patients still receive at least 40 mg/alternate dose corticosteroids. Four patients received combination therapy with methotrexate, sulphasalazine, and hydroxychloroquine and one patient received inXiximab. Lamivudine was not stopped in any of the patients because of adverse events and it was well tolerated.
Discussion In the present study, prophylactic administration of lamivudine to patients infected with HBV, who required immunosuppressive therapy, was shown to be safe, well tolerated and eVective in preventing HBV reactivation. Reactivation of hepatitis B in patients with chronic HBV infection is part of natural history of HBV and can occur spontaneously with an estimated incidence of 7.3% [5]. However, viral reactivation in HBV carriers undergoing immunosuppressive therapy ranges from 14 to 50% [2]. Reactivation of HBV was reported in 15 patients with rheumatic disease under immunosuppressive therapy in the English literature. Five of these patients were receiving a biological agent such as inXiximab. Three patients died (they received non-biological therapy) and seven patients were treated preemptively with lamivudine [3, 12]. Several therapeutic options have been proposed to reduce the risk of reactivation of hepatitis B, such as prophylactic antiviral therapy and steroid free immunosuppressive regimens. Corticosteroids are the most important predisposing factor to HBV reactivation. HBV DNA contains a glucocorticoid-responsive element, and it is responsible for increased HBV DNA transcriptional activity [6, 7]. In a comparative trial, Xare-ups occurred in 47.7% of cases compared with 8.3% in HBV carriers with non-Hodgkin
Rheumatol Int (2009) 29:777–780
779
Table 1 Demographic and laboratory features of patients Patient Age/sex Diagnosis Disease Traetment number duration regimens
HBsAg HbsAg HBeAg Anti-HBs Anti-HBc Lamivudin HBV DNA (+) duration duration value (IU/ml)
1
43/M
PM
27
Steroida 4.5 g Azt 150 mg/day
+
27
¡
¡
+
27
At baseline: 0 2 months: 8 15 months: 352
2
73/F
SLE
108
Steroid 20 g Azt 50 mg/day HQ 200 mg/day
+
108
+
¡
+
22
At baseline: 1145 12 months: 335 21 months: 1,620
3
60/M
HSP
16
Steroid 16 g/day Cyc pulse
+
16
¡
¡
NS
16
At baseline: 0 1 months: 0 6 months: 0 10 months: 11 14 months: 942
4
55/M
SLE
9
Steroid 12 g Cyc pulse
+
9
¡
¡
NS
8
At baseline: 0 6 months: 0
5
27/F
TA
36
Steroid 6 g Cyc pulse
+
36
¡
¡
¡
22
At baseline: 0 22 months: 0
6
33/M
AS
24
Mtx 15 mg/week Szp 3 g/day HQ 200 mg/day
+
122
¡
¡
+
5
At baseline: 0 5 months: 0
7
47/M
RA
12
Mtx 15 mg/week HQ 100 mg/day
+
120
¡
¡
+
12
At baseline: 27 10 months: 3,670
8
32/F
RA
12
Mtx 15 mg/week Szp 3gr/day HQ 200 mg/dl
+
38
¡
¡
+
10
At baseline : 11 4 months: 7 7 months: 0
9
53/M
AS
178
Ãnf 5 mg/kg/6 weeks +
5
¡
¡
+
5
At baseline: 0 2 months: 43 5 months: 0
10
61/F
RA
80
Mtx 15 mg/week HQ 200 mg/day Szp 2g/day Lef 10 mg/day
+
16
NS
¡
+
16
At baseline: 0 4 months: 0 10 months: 0
11
39/F
AS
52
Mtx 10 mg/week HQ 100 mg/day Szp 2g/day
+
90
¡
+
+
9
At baseline: 0 9 months: 0
Durations are indicated as months Azt Azatiopurine, HQ hydroxychloroquine, Cyc pulse cyclic 500 mg pulse cyclophosphamide, Mtx methotrexate, Szp sulphasalazine, Ãnf inXiximab, Lef leXunamide, PM polymyositis, SLE systemic lupus erythematosus, HSP Henoch-Schonlein purpura, TA Takayasu arteritis, RA rheumatoid arthritis, AS ankylosing spondylitis, NS not studied a Total steroid dose
lymphoma treated with corticosteroid-containing and corticosteroid-free chemotherapy, respectively [8]. Recently, several reports have shown promising results for lamivudine clinical prophylaxis in HBV positive cancer patients before and during chemotherapy [4]. Lamivudine usually induces a rapid reduction in HBV replication within a few weeks of treatment, and the eVect is maintained throughout treatment up to 1 year. The toxicity proWle of lamivudine is favorable because it does not overlap with that of immunosuppressive agents, making this agent particularly suitable for a simultaneous use with immunosuppressive therapy [4]. We did not observe any hematologic or other toxicity during the treatment.
Nevertheless, long-term therapy with lamivudine has been shown to induce resistance in the form of mutations in the tyrosine, methionine, aspartate, aspartate (YMDD) locus. The rate of virological breakthrough due to YMMD mutant strains has been estimated at 15–30% at year 1, 40% at year 2, 50% at year 3, and 60% at year 4 of treatment [9]. Recent meta-analysis of lamivudine treatment in renal transplant recipients with chronic HBV infection showed a rate of lamivudine resistance that ranged between 10 and 42% [10]. Although lamivudine is eVective in HbsAg positive cancer patients, the duration of treatment in these patients is limited. However, in rheumatologic diseases such as RA the duration of treatment is usually lifelong.
123
780
Tapering of steroids in SLE and vasculitis patients usually lasts 1–2 years. Also, HBV reactivation occurs mainly following cessation of immunosuppressive treatment. Lamivudine resistance was signiWcantly and positively associated with prolonged drug use. In SLE and vasculitic patients under lamivudine prophylaxis, the dangerous period for HBV reactivation seems to occur 2 years later. In our study median duration of lamivudine use was 12.3 months and Wve of ten patient’s follow-up duration was 1 year or more (Table 1). Four of these Wve patients’ HBV DNA values increased during follow-up. At the beginning, patient number 2’s HBV DNA was high (1145 IU/ml); 8 months later, HBV DNA value decreased (335 IU/ml). However, 22 months later, HBV DNA value again increased (1,620 IU/ml). Three patients’ HBV DNA values were normal at baseline and increased at follow-up (1.pt#, 3.pt# and 7.pt#, 352, 992 and 3,670 IU/ml, respectively). In our study, one patient received inXiximab for AS. In the literature three patients under inXiximab therapy had reactivation of HBV and only one patient received preemptive lamivudine prophylaxis before inXiximab therapy with no evidence of HBV reactivation. HBV-induced liver inXammation is predominantly immune mediated and TNF has antiviral activity in liver [3]. We suggest that co administration of antiviral therapy such as lamivudine with anti-TNF therapy, especially inXiximab, may be suitable for HBV carriers. Our study has some limitations. First, our study is a retrospective and small study. Second, the treatment regimens, steroid dosages, and diseases are not homologous. Third, reports have also suggested possible reactivation of HBV in patients who are HbsAg (¡), for example, in anti-HBc (+)/ HbsAg (¡)/anti-HBs (¡) patients with or without HBV DNA by PCR [11]. However, we only prescribed lamivudine in HbsAg positive patients. There are some unanswered questions about lamivudine prophylaxis in patients with a rheumatological disorders undergoing immunosuppresive therapy, which are as follows a.
The optimal duration of lamivudine therapy and the timing of treatment withdrawal. b. How should we screen patients about lamivudine resistance? c. What should we do in patients with increase HBV DNA value on follow-up? d. Are there any diVerences with or without steroidcontaining regimens for prophylaxis regimens and follow-up?
123
Rheumatol Int (2009) 29:777–780
All the unresolved problems above could only be solved by further prospective placebo-controlled trials including larger number of patients.
References 1. Mehmet D, Meliksah E, Serif Y, Gunay S, Tuncer O, Zeynep S (2005) Prevalence of hepatitis B infection in the southeastern region of Turkey: comparison of risk factors for HBV infection in rural and urban areas. Jpn J Infect Dis 58(1):15–19 2. Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, Hui P, Leung NW, Zee B, Johnson PJ (2000) Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identiWcation of risk factors. J Med Virol 62(3):299–307 3. Calabrese LH, Zein NN, Vassilopoulos D (2006) Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 65(8):983–989 4. Vassiliadis T, Garipidou V, Tziomalos K, Perifanis V, Giouleme O, Vakalopoulou S (2005) Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy a prospective case series. Am J Hematol 80(3):197–203 5. Gupta S, Govindarajan S, Fong TL, Redeker AG (1990) Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 12(5):562–568 6. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA (1986) Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci USA 83(6):1627–1631 7. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, Kao WY, Uen WC, Hsu CH, Tien HF, Chao TY, Chen LT, WhangPeng J (2003) Lymphoma Committee of Taiwan Cooperative Oncology Group Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 37(6):1320–1328 8. Cheng AL (1996) Steroid-free chemotherapy decreases the risk of hepatitis Xare-up in hepatitis B virus carriers with non-Hodgkin’s lymphoma. Blood 87(3):1202 9. Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, Rizzetto M, Craxi A (2004) Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 40(4):883–891 10. Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P (2004) Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: meta-analysis of clinical trials. Transplantation 77(6):859–864 11. Berger A, Preiser W, Kachel HG, Sturmer M, Doerr HW (2005) HBV reactivation after kidney transplantation. J Clin Virol 32(2):162–165 12. Tsai FC, Hsieh SC, Chen DS, Sheu JC, Chen DS (2006) Reactivation of hepatitis B virus in rheumatologic patients receiving immunosuppressive agents. Dig Dis Sci 51:1627–1632
