Individual studies and clinical reviews have suggested that preventive lamivudine therapy reduces reactivation of hepatitis B in persons who test positive for HBsAg and are undergoing chemotherapy, but the overall benefits of this approach have not been fully assessed quantitatively (8
). This research synthesis revealed that preventive lamivudine reduces the risk for HBV reactivation and HBV-related hepatitis by 79% or more. In addition, preventive lamivudine may reduce the risk for HBV-related hepatic failure and death in patients who test positive for HBsAg and receive chemotherapy. The magnitude of benefits for both the primary and secondary outcomes seemed to be independent of study design, such as randomized, controlled versus nonrandomized; prospective cohort studies versus retrospective cohort studies; concurrent versus historical controls; and use of no lamivudine versus deferred lamivudine controls. Because the overall methodological quality of the studies included in this review was relatively weak, some bias may exist, and the true benefits may not be as extreme as reported here. Therefore, it is justifiable to suggest that lamivudine seems to decrease risk for HBV reactivation and its complications and may be considered in all persons who test positive for HBsAg and are undergoing chemotherapy. A recent statement from an expert panel supports these recommendations (5
Because chronic hepatitis B and the HBsAg carrier state are frequently silent, it seems appropriate that all persons who have a high- or intermediate-risk for exposure to HBV be screened for HBsAg before cancer treatment is initiated (29
). This is especially important in immigrants from (and in populations of) Asia, Africa, and parts of South America and Eastern Europe, where HBV prevalence may be as high as 5% to 15% of the general population, and in men who have sex with men (28
Because up to one third of the general population could develop cancer during their lifetime (10
), a large proportion of persons worldwide will probably receive chemotherapy. Thus, patients who test positive for HBsAg are at increased risk for HBV-related morbidity and mortality due to HBV reactivation. Results of this research synthesis, even with a possible bias toward higher-than-real benefits, support preventive lamivudine therapy as the preferred approach over no or deferred lamivudine. The optimal duration of preventive lamivudine therapy has not yet been conclusively determined, although maintenance lamivudine for 6 months after discontinuing chemotherapy has been recommended in recent guidelines published by the American Association for the Study of Liver Diseases (28
). Hsu and coworkers (23
) proposed that preventive lamivudine treatment be continued for at least 8 months after completion of chemotherapy (23
). Although lamivudine therapy reduces the risk, HBV reactivation and death remain a possibility (29
). The efficacy of long-term lamivudine therapy is limited by the appearance of antiviral resistance (5
). For these reasons, preventive use of recently available, potent anti-HBV agents (such as entecavir, telbuvidine, adefovir, and tenofovir ) might be preferable to further reduce the risk for morbidity and mortality in high-risk patients. These newer agents, however, are more expensive than lamivudine, and their long-term safety is less well defined. Large, prospective, and well-designed randomized, controlled studies are needed to address this issue.
Although results of our research synthesis provide important evidence that supports the use of preventive lamivudine in a chemotherapy setting, several limitations exist. The clinical trials included in this study were limited by small sample sizes; heterogeneity of patient populations, baseline demographic characteristics or viral-host factors, and type of chemotherapeutic regimens used; and variable duration of treatment and follow-up, all of which may limit the overall treatment effects. Most studies were retrospective cohort studies or prospective cohort studies that had either a historical or a concurrent control group. In addition, 1 study was available only as an abstract and only 2 studies had a randomized, controlled design. Although such heterogeneity could increase the generalizability of our findings, the potential for bias prevented use of pooled estimates of study outcomes. Despite these limitations, the treatment effect was unidirectional in favor of preventive lamivudine therapy. Most relevant clinical trials were probably identified by a search of various major literature retrieval databases in all languages covering the entire period when lamivudine was available for clinical use.
Because of study limitations and unavailability of data, we could not address several important questions. Previous studies have suggested that persons with a higher risk for HBV reactivation include those with cirrhosis and high baseline HBV DNA levels, as well as those receiving corticosteroids or chemotherapy containing rituximab (30
). Because of a lack of comprehensive data in most studies, we could not reliably assess these factors. We did not do covariate adjustment because of small sample sizes and lack of standardization in reporting outcomes among studies based on important baseline characteristics, such as age, sex, race or ethnicity, or pretreatment serum ALT and HBV DNA levels. Although lamivudine therapy clearly should be initiated before immunosuppressive therapy (28
), the optimal duration of therapy remains to be studied. An exacerbation of disease can follow discontinuation of lamivudine therapy in patients with chronic hepatitis B and high levels of HBV DNA (32
). For these reasons, patients with chronic hepatitis B who have elevated serum ALT levels and high levels of HBV DNA in serum before initiation of chemotherapy may require long-term therapy for the underlying hepatitis B (5
). Premature withdrawal of lamivudine after chemotherapy has been associated with HBV reactivation and, on rare occasions, could be fatal. Therefore, close follow-up of patients with serial (measured every 1 to 2 months) serum ALT levels and HBV DNA levels for 3 to 6 months after preventive lamivudine therapy is discontinued is advised. Prompt recognition of increased serum HBV DNA levels warrants reinstitution of lamivudine. Most experts would not discontinue lamivudine therapy in persons who have persistently elevated serum ALT and detectable serum HBV DNA levels by polymerase chain reaction and may consider long-term treatment options in these patients.
Other issues not addressed in this research synthesis include use of preventive lamivudine therapy in other situations requiring immunosuppression, such as during therapy for rheumatologic and autoimmune disorders (particularly with the use of high-dose corticosteroids and agents that are active against tumor necrosis factor-α
) and after bone marrow or solid-organ transplantation (5
). Also of great importance is whether patients with antibodies to HBV (antibody to hepatitis B core antigen) without HBsAg should receive preventive antiviral therapy if they are immunocompromised, such as during chemotherapy or other immunosuppressive therapy, or if they have diseases associated with progressive immunodeficiency, such as chronic HIV infection (5
Lamivudine has a good safety record, and according to this research synthesis, preventive lamivudine therapy may reduce both HBV-related morbidity and mortality in patients who test positive for HBsAg and are undergoing chemotherapy. Despite the limitations of the studies included in this review, it seems justifiable to suggest that persons who have a high- or intermediate-risk for exposure to hepatitis B be identified and screened for HBsAg before chemotherapy is initiated. All patients who test positive for HBsAg and are undergoing chemotherapy should be considered for preventive lamivudine therapy (5
). Although the optimal duration of treatment remains inconclusive, most experts recommend starting lamivudine therapy before chemotherapy and continuing treatment for at least 6 months or more after stopping chemotherapy (28
). Large, randomized, controlled studies are needed to establish the exact duration of preventive anti-HBV therapy and to define the clinical role and efficacy of newer anti-HBV agents, such as entecavir, telbuvidine, adefovir, and tenofovir.