Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
![]() |
Abstract |
---|
Keywords: hepatitis B virus , 3TC , antiviral
![]() |
Hepatitis B virus |
---|
Geographical patterns of HBV prevalence vary greatly, with areas of low endemicity (HBV carriage rate, < 2%) to areas of high endemicity (HBV carriage rate, > 7%).2 The prevalence of HBV surface antigen (HBsAg) positivity in Turkey averages 5%, being lower in western regions (3.9%) and higher in eastern regions (12.5%) of the country.3 The prevalence of HBsAg-positive individuals requiring haematopoietic cell transplantation has been reported to be 1% in American recipients, 3.5% in European recipients and 9% in Turkish recipients.35
HBV infection is associated with a spectrum of clinical presentations that vary as a function of age and the immunological status of the infected individuals. More than 90% of adult immunocompetent adults who become infected clear the infection, whereas disease chronicity occurs in individuals who are immunocompromised for any reason. Histologically, HBV-induced liver disease varies from a near normal liver to an aggressive chronic hepatitis, which can occur with/without cirrhosis and in some cases hepatic cancer.1,6 HBsAg carriers with normal aminotransferases levels and normal/minimal hepatic histological changes are typically anti-HBe-positive and anti-HBc IgM negative, and have low HBV-DNA levels (in the range 103105 copies/mL); they constitute a large proportion of the HBV-infected populations. These individuals have inactive disease characterized by prolonged phases of inactive HBV replication and apparent quiescence of their liver disease, alternating with phases of viral reactivation and exacerbation of the hepatic disease.
The primary goal of therapy for HBV infection is the sustained eradication of viral replication, the elimination of any biochemical and histological hepatitis and the prevention of subsequent HBV-related morbidity and mortality. Currently, of the available anti-HBV drugs, lamivudine (3TC) is the only nucleoside (cytosine) analogue that has been used widely for the treatment of HBV infection.7 Lamivudine is a reverse-transcriptase inhibitor of viral DNA polymerase.7 The active drug is a phosphorylated metabolite, which has potent antiviral activity against HBV.7 Numerous studies have shown that lamivudine therapy of chronic hepatitis B results in clinical, biochemical and serological resolution of the HBV infection in immunocompetent individuals.7,8 It is a remarkably safe drug, only rarely manifesting mild adverse effects. Unfortunately, the effectiveness of long-term lamivudine treatment decreases progressively as a result of the emergence of resistant mutant HBV strains. Emergence of lamivudine-resistant HBV is associated with viral load rebound and results in a higher rate of liver disease progression.7
![]() |
HBV reactivation |
---|
|
Although it is well known that chemo/immunosuppressive therapy enhances viral replication,912 the role of prophylactic antiviral therapy to prevent chemo/immunosuppressive therapy-induced HBV reactivation in candidates for such therapy is less established and remains controversial.
![]() |
Lamivudine used as prophylaxis of HBV reactivation |
---|
|
In contrast, 50% of the individuals in the control group demonstrated evidence of HBV reactivation. At the time of reactivation, four of these subjects were actively receiving chemotherapy. The one remaining individual had completed her course of chemotherapy at the time of reactivation. This rate of HBV reactivation in the control group is comparable with that reported in other studies (Table 2).1517 But in contrast to Lim et al.,16 who reported a high HBV-related-mortality (26%) in HBV carriers who receive chemotherapy, no HBV-related mortality was observed in our group.18 Based on these results, inactive HBV carriers who receive chemotherapy should be placed on lamivudine prophylaxis.
![]() |
Treatment of HBV reactivation |
---|
The effectiveness of lamivudine in the treatment of HBV reactivation in individuals with haemato-oncological malignancy has been proven in a number of reports;14,20,21 however, low efficacy of lamivudine treatment has also been reported in a small series.22 Responding individuals showed clinical, biochemical and serological improvement. The previous studies have shown that lamivudine treatment was life-saving in transplant recipients with HBV reactivation, whereas prognosis of recipients with HBV reactivation who did not receive lamivudine was dismal.4,23 In our work, lamivudine was administered to all individuals with HBV reactivation, including those in the control group. On lamivudine treatment, the liver injury abnormalities characteristic of HBV reactivation fell to normal levels within 2 weeks2 months after the initiation of lamivudine treatment. HBV-DNA became undetectable in all individuals receiving lamivudine therapy. Once the liver injury tests were normal and HBV-DNA was undetectable, the chemotherapy regimens were restarted.18
![]() |
Duration of lamivudine therapy |
---|
![]() |
Side effects of lamivudine therapy |
---|
According to published data, the risk of developing lamivudine-resistant HBV increases with the duration of lamivudine treatment.7 Most cases of resistance are associated with mutations in the YMDD motif of the polymerase gene.7 Resistance rates between 1540% have been reported after 2 years of lamivudine treatment in immunocompetent individuals with chronic HBV infection.7 In immunosuppressive individuals, Chan et al.23 reported a cumulative resistance rate of 41% after 31 months in HBsAg-positive kidney allograft recipients receiving lamivudine.23 Lau et al.4 reported only one allogeneic haematopoietic cell transplant (1/20) case treated with lamivudine who developed lamivudine resistance at week 40. Rossi et al.15 reported that no HBV carrier with lymphoid malignancies treated with chemotherapy developed lamivudine resistance during a limited duration of lamivudine prophylaxis (1 month after completion of the chemotherapy cycles).15 None of the individuals we studied with haematological malignancy who received lamivudine has developed a lamivudine-resistant virus after a mean of 14 months of continuous lamivudine therapy.
The development of HBV resistance has been a factor limiting the durability of the therapeutic effectiveness of lamivudine treatment. Adefovir dipivoxil, a monophosphate nucleotide analogue, was approved by the United States Food and Drug Administration and represents the newest approach to the treatment of HBV infection.24 In contrast to lamivudine, there is lack of viral resistance with prolonged therapy with adefovir dipivoxil in immunocompetent individuals.24 Moreover, adefovir is effective against the HBV mutant virus. There are no data available concerning the efficacy, safety and tolerability of adefovir dipivoxil when used to treat lamivudine-resistant HBV reactivation in individuals with haemato-oncological malignancies. Additional studies are needed to clarify the role of adefovir dipivoxil in immunosuppressed individuals, to define its efficacy and to identify any adverse haematological side effects.
![]() |
Current status of lamivudine therapy |
---|
![]() |
In conclusion |
---|
![]() |
Acknowledgements |
---|
![]() |
References |
---|
2 . Maddrey, W. C. (2000). Hepatitis B. An important public health issue. J Med Virol 61, 3626.
3 . Ustün, C., Koc, H., Karayalcin, S. et al (1997). Hepatitis B virus infection in allogeneic bone marrow transplantation. Bone Marrow Transplant 20, 28996.[CrossRef][ISI][Medline]
4 . Lau, G. K. K., He, M., Fong, D. Y. T. et al. (2002). Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology 36, 7029.[CrossRef][ISI][Medline]
5 . Locasciulli, A., Alberti, A., de Bock, R. et al. (1994). Impact of liver disease and hepatitis infections on allogeneic bone marrow transplantation in Europe. Bone Marrow Transplant 14, 8337.[ISI][Medline]
6 . Fattovich, G., Brollo, L., Giustina, G. et al. (1991). Natural history and prognostic factors for chronic hepatitis type B. Gut 32, 2948.
7 . Papatheodoridis, G. V., Dimou, E. & Papadimitropoulos, V. (2002). Nucleoside analogues for chronic hepatitis B: antiviral efficacy and viral resistance. Am J Gastroenterol 97, 161828.[CrossRef][ISI][Medline]
8
.
Dienstag, J. L., Schiff, E. R., Wright, T. L. et al. (1999). Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 341, 125663.
9 . Hoofnagle, J. H., Dusheiko, G. M., Schafer, D. F. et al. (1982). Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 96, 4479.[ISI][Medline]
10 . Steinberg, J. L., Yeo, W., Zhong, S. et al. (2000). Hepatitis B virus reactivation in patients undergoing cytotoxic chemotherapy for solid tumors: precore/core mutations may play an important role. J Med Virol 60, 24955.[CrossRef][ISI][Medline]
11 . Yeo, W., Chan, P. K. S., Zhong, S. et al. (2000). Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy. J Med Virol 62, 299307.[CrossRef][ISI][Medline]
12
.
Tur-Kaspa, R., Burk, R. D., Shaul, Y. et al. (1986). Hepatitis B virus contains a glucocorticoid-responsive element. Proc Natl Acad Sci USA 83, 162731.
13 . McMillan, J. S., Shaw, T., Angus, P. W. et al. (1995). Effect of immunosuppressive and antiviral agents on hepatitis B virus replication in vitro. Hepatology 22, 3643.[CrossRef][ISI][Medline]
14 . Rossi, G. (2003). Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy. Leukemia and Lymphoma 44, 75966.[CrossRef]
15 . Rossi, G., Pelizzari, A., Motta, M. et al. (2001). Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HBsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 115, 5862.[CrossRef][ISI][Medline]
16 . Lim, L. L., Wai, C. T., Lee, Y. M. et al. (2002). Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Aliment Pharmacol Ther 16, 193944.[CrossRef][ISI][Medline]
17
.
Shibolet, O., Ilan, Y., Gillis, S. et al. (2002). Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 100, 3916.
18 . Idilman, R., Arat, M., Soydan, E. et al. (2004). Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies. J Viral Hepatitis 11, 1417.[CrossRef][ISI][Medline]
19 . Lau, G. K. K., Liang, R., Wu, P. C. et al. (1998). Use of famciclovir to prevent HBV reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation. J Hepatol 28, 35968.[CrossRef][ISI][Medline]
20 . Ahmed, A. & Keeffe, E. B. (1999). Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B infection. Am J Gastroenterol 94, 24951.[CrossRef][ISI][Medline]
21 . Uchida, N., Gondo, H., Himeji, D. et al. (2000). Lamivudine therapy for a hepatitis B surface antigen positive leukemia patient receiving myeloablative chemotherapy and autologous stem cell transplantation. Bone Marrow Transplant 26, 12435.[CrossRef][ISI][Medline]
22 . Cainelli, F., Longhi, M. S., Concia, E. et al. (2001). Failure of lamivudine therapy for chemotherapy-induced reactivation of hepatitis B. Am J Gastroenterol 96, 16512.[CrossRef]
23 . Chan, T. M., Fang, G. X., Tang, C. S. O. et al. (2002). Preemptive lamivudine therapy based on HBV-DNA level in HBsAg-positive kidney allograft recipients. Hepatology 36, 124652.[CrossRef][ISI][Medline]
24 . Qaqish, R. B., Mattes, K. A. & Ritchie, D. J. (2003). Adefovir dipivoxil: a new antiviral agent for the treatment of hepatitis B virus infection. Clin Therap 25, 308499.[CrossRef][ISI][Medline]
|