Clin J Gastroenterol (2009) 2:210–213 DOI 10.1007/s12328-009-0065-0
CASE REPORT
Successful cessation of lamivudine using interferon in a patient with chronic hepatitis B who received prophylactic lamivudine treatment during chemotherapy Kazuhiko Hayashi Æ Yoshiaki Katano Æ Masatoshi Ishigami Æ Akihiro Itoh Æ Yoshiki Hirooka Æ Isao Nakano Æ Hidemi Goto
Received: 25 September 2008 / Accepted: 12 December 2008 / Published online: 19 March 2009 Ó Springer 2009
Abstract Lamivudine (LMV) prophylaxis is effective in preventing hepatitis B virus (HBV) reactivation in patients with chronic hepatitis B undergoing chemotherapy. However, the optimal duration of LMV prophylaxis remains unclear. We report herein the case of a woman with localized follicular B-cell lymphoma who received chemotherapy with LMV prophylaxis. She achieved complete response to lymphoma, and LMV treatment was continued for 8 months after completion of chemotherapy. HBV status was still inactive. LMV was then stopped, but reactivation of hepatitis developed 1 month after cessation of LMV. LMV was restarted, resulting in successful treatment of reactivated hepatitis. Interferon (IFN) was used for 6 months before withdrawal of LMV, which was successfully ceased without flare hepatitis. This report describes the utility of sequential therapy with LMV and IFN to treat flare after withdrawal of LMV in hepatitis B carriers who receive LMV prophylaxis during chemotherapy and to prevent flare after withdrawal of LMV. Keywords
active hepatitis, and progression to cirrhosis and hepatocellular carcinoma [2]. Immunosuppression caused by chemotherapeutic and immune-modulating agents can induce HBV reactivation in infected patients [3–5], and HBV reactivation frequently progresses to fatal hepatic failure [3–6]. Prophylactic antiviral therapy using lamivudine (LMV) has been recommended and should be used in hepatitis B carriers undergoing chemotherapy [7, 8]. The increasing rate of drug resistance during long-term LMV treatment is of major concern [9–11], but hepatitis flare after LMV withdrawal has been reported [12–14]. The optimal duration of LMV prophylaxis is thus difficult to define. LMV prophylaxis is recommended to be continued for C6–12 months after completion of chemotherapy [7]. However, hepatitis flare may occur in a small population despite this recommendation. We report herein the effectiveness of interferon (IFN) in preventing hepatitis flare after withdrawal of LMV in a hepatitis B carrier receiving prophylaxis LMV during chemotherapy.
Hepatitis B virus Interferon Prophylaxis Case report
Introduction About 350 million people globally are infected with hepatitis B virus (HBV) [1]. This infection displays a variety of clinical courses, such as inactive carrier state, chronic
K. Hayashi Y. Katano (&) M. Ishigami A. Itoh Y. Hirooka I. Nakano H. Goto Department of Gastroenterology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected]
123
A 39-year-old Japanese woman was found to be suffering from localized follicular B-cell lymphoma stage IA in 2004. The patient had a history of chronic hepatitis B at 22 years old. In 1996, she had received IFN therapy and finally achieved normalization of liver enzymes, HBe antigen (Ag)-negative and anti-HBe antibody-positive status, and undetectable levels of HBV. She routinely received annual health checkups and had maintained inactive carrier status until admission to our hospital. Laboratory data at the initiation of chemotherapy are shown in Table 1. According to guidelines [7, 8], we started preemptive use of LMV (Zefix, GlaxoSmithKline,
Clin J Gastroenterol (2009) 2:210–213
Discussion Patients with HBV infection who receive chemotherapy are at high risk of fatal liver failure induced by HBV reactivation [3–6]. LMV prophylaxis is effective for reducing the risk of HBV reactivation and has been recommended for
Table 1 Laboratory data at the initiation of chemotherapy WBC
7,100/ll
Na
140 Eq/l
RBC
3.61 9 104/ll
K
3.8 Eq/l
Hb
10.5 g/dl
Cl
102 Eq/l
Ht
33.1%
BUN
7 mg/dl
Plt
23.4 9 104/ll
Cre
0.5 mg/dl
AST
13 IU/l
Glu
99 mg/dl
ALT
6 IU/l
PT
106%
T.Bil
0.3 mg/dl
HCV Ab
(-)
c-GTP
13 IU/l
HBs Ag
(?)
LDH
216 IU/l
HBe Ag
(-)
ALP
216 IU/l
HBe Ab
(?)
Cho
210 mg/dl
HBc Ab
(?)
TP
6.9 g/dl
HBs Ab
(-)
Alb
3.9 g/dl
HBV-DNA
\2.6 log/ml
IFN LMV
LMV
HBV(log copies/ml)
R-CHO
ALT/AST(U/L)
UK) at 100 mg/day before chemotherapy. In November 2004, she was treated with cyclophosphamide, doxorubicin, and vincristine with rituximab chemotherapy, resulting in complete remission. Liver-specific enzymes were almost normal and HBV-DNA was persistently negative during chemotherapy. LMV prophylaxis was effective in preventing reactivation of HBV infection. The clinical course is shown in Fig. 1. According to American Association for the Study of Liver Diseases (AASLD) recommendation [7], LMV treatment was continued for 6 months after completion of chemotherapy. In March 2006, 8 months after end of chemotherapy, HBV status was still inactive. LMV was stopped and the patient was carefully followed. In April, HBV-DNA was identified (3.8 log10 copies/mL, Amplicor Monitor; Roche Molecular Systems, Branchburg, NJ), but alanine aminotransferase (ALT) level was normal. At this time, investigation of the HBV sequence revealed genotype Ce with basal core promoter/precore mutations such as A1762T, G1764A, and G1896A. Mutations L180 M or M204 V/I in the polymerase region, which are known to be associated with resistance to LMV, were absent. In May, the patient felt fatigued and consulted our outpatient clinic. At this time, HBV-DNA was rapidly increased (7.1 log10 copies/ml) and liver enzymes were markedly elevated [aspartate aminotransferase (AST), 1815 U/L; ALT, 2010 U/L; c-glutamyl transpeptidase, 65 U/L]. These data are summarized in Table 2. Flare was considered to have occurred, so LMV was restarted. HBVDNA became undetectable and liver function recovered after 1 month. After 3 months of LMV treatment, IFN 500 MU/day (OIF; Otsuka Pharmaceuticals, Tokyo, Japan) was added at a dose of 500 MU three times per week. Neutropenia (500 cells/mm3) was found at 1 week after the start of LMV and IFN combination treatment, then IFN was reduced to 250 MU and continued for 3 months. Treatment was then replaced by IFN alone for 3 months. Overall treatment course was thus LMV monotherapy for 3 months, followed by LMV and IFN combination therapy for 3 months, and a final IFN monotherapy for 3 months. HBV-DNA and HBV core-related antigen (HBcrAg) were undetectable at the end of treatment. The patient displayed a persistently low level of serum HBV-DNA and normal serum ALT and AST levels during IFN therapy and at 24 weeks after withdrawal of IFN treatment. Finally, she was defined as a virologic responder.
211
Fig. 1 Clinical course of patient
patients undergoing chemotherapy [7, 8]. The present case demonstrates the usefulness of LMV prophylaxis in preventing HBV reactivation during chemotherapy in a patient with HBV infection. The optimal duration of LMV prophylaxis remains unclear. LMV has been used for several weeks after withdrawing chemotherapy in some reports [12, 15, 16]. Other reports have continued LMV for several months [14, 16–18]. Flare of hepatitis including fulminant hepatic failure after cessation of LMV represents a major problem [6]. Conversely, prolonged treatment with LMV has led to the emergence of LMV-resistant strains of HBV that induce clinical flare of hepatitis. The underlying mutations occur in the HBV polymerase region, and the rate of mutant strains is reportedly about 70% after 4 years of treatment with LMV in immunocompetent patients with chronic hepatitis B [9–11]. The optimal duration of LMV prophylaxis should be the minimum duration required to prevent reactivation of hepatitis without emergence of LMV-resistant mutations during chemotherapy and without
123
212
Clin J Gastroenterol (2009) 2:210–213
Table 2 Laboratory data at 8 weeks after withdrawal of lamivudine prophylaxis WBC
3,600/ll
BUN
11 mg/dl
RBC
4.08 9 104/ll
Cre
0.5 mg/dl
Hb
13 g/dl
Glu
87 mg/dl
Ht
40.0%
PT
80.3%
Plt
7.7 9 104/ll
HBV genotype
Ce
AST
1,815 IU/l
HBs Ag
(?)
ALT
2,010 IU/l
HBe Ag
(-)
T.Bil
0.9 mg/dl
HBe Ab
(?)
c-GTP
65 IU/l
HBc Ab
(?)
LDH
998 IU/l
HBs Ab
(-)
ALP Cho
304 IU/l 216 mg/dl
HBV-DNA HBV core-related antigen
7.1 log/ml 6.2 logU/ml
TP
7.0 g/dl
Alb
4.3 g/dl
Na
141 Eq/l
K
4.3 Eq/l
Cl
104 Eq/l
flare after discontinuation of LMV. This end point is difficult to define, as predictive markers of relapse after cessation of LMV are lacking. Inactive carriers (HBeAgnegative, anti-HBe-positive patients with normal ALT levels and HBV-DNA undetectable by PCR) represent good candidates for ending administration of LMV without flare, but this criterion was not met in our case. Hui et al. observed de novo hepatitis B in HBsAg-negative patients who were receiving chemotherapy and speculated that damage to the immune system caused by chemotherapy would need 6–8 months after completion of chemotherapy for recovery in order to be able to control HBV infection [19]. Recently, they found that dysfunction of HBV immunity by chemotherapy would persist until 9 months after the end of chemotherapy, and recommended that preemptive LMV should be continued until 9 months after withdrawal of chemotherapy [20]. These concepts are useful not only for HBsAg-negative patients but also for HBsAg-positive patients when determining the duration of LMV prophylaxis. HBcrAg levels offer a predictor of the risk of flare hepatitis after LMV withdrawal [21]. We were able to retrospectively check HBcrAg at the onset of reactivation and the end of LMV ? IFN therapy. The level of HBcrAg at the end of LMV ? IFN therapy was under the limit of detection. HBcrAg assay would thus help to identify patients able to discontinue LMV without fatal HBV reactivation. However, measurement of HBcrAg at prophylactic LMV cessation was not performed in the present case and was insufficient to prove the usefulness of HBcrAg. Readministration of LMV was thus one option,
123
but another strategy is needed for this subpopulation of patients in whom withdrawal of LMV fails. IFN prophylaxis cannot be used during chemotherapy because of bonemarrow-suppressive effects. However, IFN appears to represent a good therapeutic option after chemotherapy. Since LMV and IFN have different mechanisms of action, LMV and IFN combination treatment may be useful. We speculated that combination treatment with LMV and IFN might have an additive effect in achieving safe discontinuation of LMV used prophylactically to prevent HBV reactivation. The effect of LMV and IFN combination treatment on immunocompetent patients with chronic hepatitis B after 24 weeks of follow-up was not significantly different from that of IFN monotherapy [22]. Sequential therapy with LMV and IFN would offer advantages over simultaneous combination therapy [23, 24]. Reduction of HBV levels by prior LMV monotherapy is thought to improve the effects of IFN by restoring T-cell reactivity, thus offering favorable conditions for IFN activity against HBV. We modified this concept and created a protocol using LMV and IFN for safe cessation of LMV. Flare hepatitis after LMV withdrawal in patients with inactive HBsAg carrier state is infrequent, and insufficient information is currently available to recommend routine use of IFN for these individuals to prevent HBV relapse after LMV withdrawal. However, HBV carriers who display flare after withdrawal of LMV used for prophylaxis during chemotherapy should try IFN for safe withdrawal of LMV, as long-term use of LMV can result in the emergence of resistance. IFN therapy has been used widely for patients with HBeAg-negative chronic hepatitis B, but this treatment is conducted for a minority of patients in Japan because IFN is not yet covered by medical insurance. The present case indicates the effect of IFN in preventing flare after LMV withdrawal in hepatitis B carriers receiving LMV prophylaxis during chemotherapy.
References 1. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis. 2002;2:395–403. 2. Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350:1118–29. 3. Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med. 1982;96:447–9. 4. Liang R, Lau GK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncology. 1999;7:394–8. 5. Yeo W, Chan PKS, Zhong S, Ho WM, Steimberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patient undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000; 62:299–307.
Clin J Gastroenterol (2009) 2:210–213 6. Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002;51:597–9. 7. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007; 45:507–39. 8. Lalazar G, Rund D, Shouval D. Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies. Br J Haematol. 2007;136:699–712. 9. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. New Engl J Med. 1999; 341:1256–63. 10. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172–80. 11. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–22. 12. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742–9. 13. Wong VW, Chan HL, Wong ML, Tam JS, Leung NW. Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants. Aliment Pharmacol Ther. 2004; 19:323–9. 14. Hui CK, Cheung WW, Au WY, Lie AK, Zhang HY, Yueng YH, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut. 2005;54:1597–603. 15. Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol. 2001;115:58–62. 16. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-
213
17.
18.
19.
20.
21.
22.
23.
24.
induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood. 2002;100:391–6. Lau GK, He ML, Fong DY, Bartholomeusz A, Au WY, Lie AK, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002;36:702–9. Idilman R, Arat M, Soydan E, To¨ru¨ner M, Soykan I, Akbulut H, et al. Lamivudine prophylaxis for prevention of chemotherapyinduced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. J Viral Hepat. 2004;11:141–7. Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung AY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131:59–68. Hui CK, Cheung WW, Leung KW, Cheng VC, Tang BS, Li IW, et al. Retracted: outcome and immune reconstitution of HBVspecific immunity in patients with reactivation of occult HBV infection after alemtuzumab-containing chemotherapy regimen. Hepatology. 2008;48:1–10. Matsumoto A, Tanaka E, Minami M, Okanoue T, Yatsuhashi H, Nagaoka S, et al. Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy. Hepatol Res. 2007;8:661–6. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682–95. Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouille`res O, Carbonell N, et al. Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study. Hepatology. 2001;34:573–7. Sarin SK, Kumar M, Kumar R, Kazim SN, Guptan RC, Sakhuja P, et al. Higher efficacy of sequential therapy with interferonalpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol. 2005;100:2463–71.
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CASE REPORT
Successful cessation of lamivudine using interferon in a patient with chronic hepatitis B who received prophylactic lamivudine treatment during chemotherapy Kazuhiko Hayashi Æ Yoshiaki Katano Æ Masatoshi Ishigami Æ Akihiro Itoh Æ Yoshiki Hirooka Æ Isao Nakano Æ Hidemi Goto
Received: 25 September 2008 / Accepted: 12 December 2008 / Published online: 19 March 2009 Ó Springer 2009
Abstract Lamivudine (LMV) prophylaxis is effective in preventing hepatitis B virus (HBV) reactivation in patients with chronic hepatitis B undergoing chemotherapy. However, the optimal duration of LMV prophylaxis remains unclear. We report herein the case of a woman with localized follicular B-cell lymphoma who received chemotherapy with LMV prophylaxis. She achieved complete response to lymphoma, and LMV treatment was continued for 8 months after completion of chemotherapy. HBV status was still inactive. LMV was then stopped, but reactivation of hepatitis developed 1 month after cessation of LMV. LMV was restarted, resulting in successful treatment of reactivated hepatitis. Interferon (IFN) was used for 6 months before withdrawal of LMV, which was successfully ceased without flare hepatitis. This report describes the utility of sequential therapy with LMV and IFN to treat flare after withdrawal of LMV in hepatitis B carriers who receive LMV prophylaxis during chemotherapy and to prevent flare after withdrawal of LMV. Keywords
active hepatitis, and progression to cirrhosis and hepatocellular carcinoma [2]. Immunosuppression caused by chemotherapeutic and immune-modulating agents can induce HBV reactivation in infected patients [3–5], and HBV reactivation frequently progresses to fatal hepatic failure [3–6]. Prophylactic antiviral therapy using lamivudine (LMV) has been recommended and should be used in hepatitis B carriers undergoing chemotherapy [7, 8]. The increasing rate of drug resistance during long-term LMV treatment is of major concern [9–11], but hepatitis flare after LMV withdrawal has been reported [12–14]. The optimal duration of LMV prophylaxis is thus difficult to define. LMV prophylaxis is recommended to be continued for C6–12 months after completion of chemotherapy [7]. However, hepatitis flare may occur in a small population despite this recommendation. We report herein the effectiveness of interferon (IFN) in preventing hepatitis flare after withdrawal of LMV in a hepatitis B carrier receiving prophylaxis LMV during chemotherapy.
Hepatitis B virus Interferon Prophylaxis Case report
Introduction About 350 million people globally are infected with hepatitis B virus (HBV) [1]. This infection displays a variety of clinical courses, such as inactive carrier state, chronic
K. Hayashi Y. Katano (&) M. Ishigami A. Itoh Y. Hirooka I. Nakano H. Goto Department of Gastroenterology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected]
123
A 39-year-old Japanese woman was found to be suffering from localized follicular B-cell lymphoma stage IA in 2004. The patient had a history of chronic hepatitis B at 22 years old. In 1996, she had received IFN therapy and finally achieved normalization of liver enzymes, HBe antigen (Ag)-negative and anti-HBe antibody-positive status, and undetectable levels of HBV. She routinely received annual health checkups and had maintained inactive carrier status until admission to our hospital. Laboratory data at the initiation of chemotherapy are shown in Table 1. According to guidelines [7, 8], we started preemptive use of LMV (Zefix, GlaxoSmithKline,
Clin J Gastroenterol (2009) 2:210–213
Discussion Patients with HBV infection who receive chemotherapy are at high risk of fatal liver failure induced by HBV reactivation [3–6]. LMV prophylaxis is effective for reducing the risk of HBV reactivation and has been recommended for
Table 1 Laboratory data at the initiation of chemotherapy WBC
7,100/ll
Na
140 Eq/l
RBC
3.61 9 104/ll
K
3.8 Eq/l
Hb
10.5 g/dl
Cl
102 Eq/l
Ht
33.1%
BUN
7 mg/dl
Plt
23.4 9 104/ll
Cre
0.5 mg/dl
AST
13 IU/l
Glu
99 mg/dl
ALT
6 IU/l
PT
106%
T.Bil
0.3 mg/dl
HCV Ab
(-)
c-GTP
13 IU/l
HBs Ag
(?)
LDH
216 IU/l
HBe Ag
(-)
ALP
216 IU/l
HBe Ab
(?)
Cho
210 mg/dl
HBc Ab
(?)
TP
6.9 g/dl
HBs Ab
(-)
Alb
3.9 g/dl
HBV-DNA
\2.6 log/ml
IFN LMV
LMV
HBV(log copies/ml)
R-CHO
ALT/AST(U/L)
UK) at 100 mg/day before chemotherapy. In November 2004, she was treated with cyclophosphamide, doxorubicin, and vincristine with rituximab chemotherapy, resulting in complete remission. Liver-specific enzymes were almost normal and HBV-DNA was persistently negative during chemotherapy. LMV prophylaxis was effective in preventing reactivation of HBV infection. The clinical course is shown in Fig. 1. According to American Association for the Study of Liver Diseases (AASLD) recommendation [7], LMV treatment was continued for 6 months after completion of chemotherapy. In March 2006, 8 months after end of chemotherapy, HBV status was still inactive. LMV was stopped and the patient was carefully followed. In April, HBV-DNA was identified (3.8 log10 copies/mL, Amplicor Monitor; Roche Molecular Systems, Branchburg, NJ), but alanine aminotransferase (ALT) level was normal. At this time, investigation of the HBV sequence revealed genotype Ce with basal core promoter/precore mutations such as A1762T, G1764A, and G1896A. Mutations L180 M or M204 V/I in the polymerase region, which are known to be associated with resistance to LMV, were absent. In May, the patient felt fatigued and consulted our outpatient clinic. At this time, HBV-DNA was rapidly increased (7.1 log10 copies/ml) and liver enzymes were markedly elevated [aspartate aminotransferase (AST), 1815 U/L; ALT, 2010 U/L; c-glutamyl transpeptidase, 65 U/L]. These data are summarized in Table 2. Flare was considered to have occurred, so LMV was restarted. HBVDNA became undetectable and liver function recovered after 1 month. After 3 months of LMV treatment, IFN 500 MU/day (OIF; Otsuka Pharmaceuticals, Tokyo, Japan) was added at a dose of 500 MU three times per week. Neutropenia (500 cells/mm3) was found at 1 week after the start of LMV and IFN combination treatment, then IFN was reduced to 250 MU and continued for 3 months. Treatment was then replaced by IFN alone for 3 months. Overall treatment course was thus LMV monotherapy for 3 months, followed by LMV and IFN combination therapy for 3 months, and a final IFN monotherapy for 3 months. HBV-DNA and HBV core-related antigen (HBcrAg) were undetectable at the end of treatment. The patient displayed a persistently low level of serum HBV-DNA and normal serum ALT and AST levels during IFN therapy and at 24 weeks after withdrawal of IFN treatment. Finally, she was defined as a virologic responder.
211
Fig. 1 Clinical course of patient
patients undergoing chemotherapy [7, 8]. The present case demonstrates the usefulness of LMV prophylaxis in preventing HBV reactivation during chemotherapy in a patient with HBV infection. The optimal duration of LMV prophylaxis remains unclear. LMV has been used for several weeks after withdrawing chemotherapy in some reports [12, 15, 16]. Other reports have continued LMV for several months [14, 16–18]. Flare of hepatitis including fulminant hepatic failure after cessation of LMV represents a major problem [6]. Conversely, prolonged treatment with LMV has led to the emergence of LMV-resistant strains of HBV that induce clinical flare of hepatitis. The underlying mutations occur in the HBV polymerase region, and the rate of mutant strains is reportedly about 70% after 4 years of treatment with LMV in immunocompetent patients with chronic hepatitis B [9–11]. The optimal duration of LMV prophylaxis should be the minimum duration required to prevent reactivation of hepatitis without emergence of LMV-resistant mutations during chemotherapy and without
123
212
Clin J Gastroenterol (2009) 2:210–213
Table 2 Laboratory data at 8 weeks after withdrawal of lamivudine prophylaxis WBC
3,600/ll
BUN
11 mg/dl
RBC
4.08 9 104/ll
Cre
0.5 mg/dl
Hb
13 g/dl
Glu
87 mg/dl
Ht
40.0%
PT
80.3%
Plt
7.7 9 104/ll
HBV genotype
Ce
AST
1,815 IU/l
HBs Ag
(?)
ALT
2,010 IU/l
HBe Ag
(-)
T.Bil
0.9 mg/dl
HBe Ab
(?)
c-GTP
65 IU/l
HBc Ab
(?)
LDH
998 IU/l
HBs Ab
(-)
ALP Cho
304 IU/l 216 mg/dl
HBV-DNA HBV core-related antigen
7.1 log/ml 6.2 logU/ml
TP
7.0 g/dl
Alb
4.3 g/dl
Na
141 Eq/l
K
4.3 Eq/l
Cl
104 Eq/l
flare after discontinuation of LMV. This end point is difficult to define, as predictive markers of relapse after cessation of LMV are lacking. Inactive carriers (HBeAgnegative, anti-HBe-positive patients with normal ALT levels and HBV-DNA undetectable by PCR) represent good candidates for ending administration of LMV without flare, but this criterion was not met in our case. Hui et al. observed de novo hepatitis B in HBsAg-negative patients who were receiving chemotherapy and speculated that damage to the immune system caused by chemotherapy would need 6–8 months after completion of chemotherapy for recovery in order to be able to control HBV infection [19]. Recently, they found that dysfunction of HBV immunity by chemotherapy would persist until 9 months after the end of chemotherapy, and recommended that preemptive LMV should be continued until 9 months after withdrawal of chemotherapy [20]. These concepts are useful not only for HBsAg-negative patients but also for HBsAg-positive patients when determining the duration of LMV prophylaxis. HBcrAg levels offer a predictor of the risk of flare hepatitis after LMV withdrawal [21]. We were able to retrospectively check HBcrAg at the onset of reactivation and the end of LMV ? IFN therapy. The level of HBcrAg at the end of LMV ? IFN therapy was under the limit of detection. HBcrAg assay would thus help to identify patients able to discontinue LMV without fatal HBV reactivation. However, measurement of HBcrAg at prophylactic LMV cessation was not performed in the present case and was insufficient to prove the usefulness of HBcrAg. Readministration of LMV was thus one option,
123
but another strategy is needed for this subpopulation of patients in whom withdrawal of LMV fails. IFN prophylaxis cannot be used during chemotherapy because of bonemarrow-suppressive effects. However, IFN appears to represent a good therapeutic option after chemotherapy. Since LMV and IFN have different mechanisms of action, LMV and IFN combination treatment may be useful. We speculated that combination treatment with LMV and IFN might have an additive effect in achieving safe discontinuation of LMV used prophylactically to prevent HBV reactivation. The effect of LMV and IFN combination treatment on immunocompetent patients with chronic hepatitis B after 24 weeks of follow-up was not significantly different from that of IFN monotherapy [22]. Sequential therapy with LMV and IFN would offer advantages over simultaneous combination therapy [23, 24]. Reduction of HBV levels by prior LMV monotherapy is thought to improve the effects of IFN by restoring T-cell reactivity, thus offering favorable conditions for IFN activity against HBV. We modified this concept and created a protocol using LMV and IFN for safe cessation of LMV. Flare hepatitis after LMV withdrawal in patients with inactive HBsAg carrier state is infrequent, and insufficient information is currently available to recommend routine use of IFN for these individuals to prevent HBV relapse after LMV withdrawal. However, HBV carriers who display flare after withdrawal of LMV used for prophylaxis during chemotherapy should try IFN for safe withdrawal of LMV, as long-term use of LMV can result in the emergence of resistance. IFN therapy has been used widely for patients with HBeAg-negative chronic hepatitis B, but this treatment is conducted for a minority of patients in Japan because IFN is not yet covered by medical insurance. The present case indicates the effect of IFN in preventing flare after LMV withdrawal in hepatitis B carriers receiving LMV prophylaxis during chemotherapy.
References 1. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis. 2002;2:395–403. 2. Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med. 2004;350:1118–29. 3. Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med. 1982;96:447–9. 4. Liang R, Lau GK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncology. 1999;7:394–8. 5. Yeo W, Chan PKS, Zhong S, Ho WM, Steimberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patient undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000; 62:299–307.
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