Systematic Review: The Effect of Preventive Lamivudine on Hepatitis B Reactivation during Chemotherapy

Context Does lamivudine prevent hepatitis B virus (HBV) reactivation among patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy? Contribution This systematic review of 14 studies found that, compared with no preventive lamivudine, lamivudine reduced HBV reactivation, HBV-related hepatitis, and HBV-related hepatic failure. Caution Studies were small and heterogeneous. Only 2 were randomized trials, and none compared lamivudine with other, newer anti-HBV agents. Implication Preventive lamivudine may reduce risk for HBV reactivation and associated death in HBsAg-positive patients with cancer who are undergoing chemotherapy. The Editors More than 350 million persons worldwide have hepatitis B virus (HBV) (1). Chronic infection with HBV is a major public health problem and is the leading cause of liver cancer in Asia and Africa (1). In the United States, the prevalence of HBV infection, defined as the presence of hepatitis B surface antigen (HBsAg) in the blood, is less than 1% but may be as high as 5% to 15% in immigrants from Asia, Africa, the Middle East, and Eastern Europe (2, 3). Infection with HBV can lead to chronic liver disease, cirrhosis, and liver cancer (4). However, many persons who continue to harbor HBV in serum and hepatocytes for many years have few (if any) clinical sequelae. These persons are considered to have the inactive HBsAg carrier state and have little evidence of liver disease, despite low levels of HBV replication in hepatocytes (5). In such individuals, immunosuppressive agents can precipitate an increase in HBV replication followed by a flare of hepatitis B that can be severe and even fatal (6). Prompt recognition and institution of anti-HBV therapy are desirable, but therapy may fail if substantial damage has already occurred (7). Because chemotherapy is highly immunosuppressive, it may cause flares of HBV in persons who carry HBsAg in their serum (7). Flares can occur despite normal serum alanine aminotransferase (ALT) levels and low levels of circulating virus before chemotherapy is started (7, 8) and may lead to high HBV-related morbidity and mortality (9). Because cancer is the second leading cause of death in the United States, a large proportion of the population may undergo chemotherapy during their lifetime (10). Therefore, even with a relatively low prevalence of the HBsAg carrier state, prevention of chemotherapy-induced HBV reactivation is an important medical problem and a public health concern. The problem is more critical in areas of the world where HBV infection is endemic (1). Lamivudine, a nucleoside analogue (11), effectively suppresses HBV replication, reduces levels of HBV DNA in serum, and improves liver injury in patients with chronic hepatitis B. Lamivudine also has an excellent long-term safety profile and is generally well tolerated (12). Several studies reported a beneficial effect of lamivudine in preventing HBV reactivation and HBV-related death in patients who tested positive for HBsAg and are undergoing chemotherapy (8, 13, 14). However, the quantitative benefits of preventive therapy with lamivudine have not been carefully defined. The magnitude of response to lamivudine for preventing morbidity and mortality in this clinical setting has direct implications for both clinicians and health policymakers. The research synthesis discussed here explored the following question: Does preventive lamivudine therapy reduce the risk for HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death in patients who test positive for HBsAg and are undergoing chemotherapy? Methods Data Sources and Searches We searched the following databases in all languages until June 2007: MEDLINE from 1966, Ovid MEDLINE from 1950, TOXNET from 1965, Scopus from 1966, Web of Science from 1955, and the Cochrane Central Register of Controlled Trials from January 1997. Index terms included hepatitis B virus or HBV in combination with reactivation. Figure 1 shows our prespecified protocol. We also did a manual review of the bibliographies for seminal primary and review articles to identify additional relevant studies. Furthermore, we manually searched the 2006 and 2007 American Gastroenterological Association annual meeting abstracts. To maximize data requisition, we contacted authors whose articles contained inadequate information. In addition, we contacted authors of included studies to request information about long-term efficacy and safety outcomes, including cancer-related or all-cause mortality, adverse effects of lamivudine, and any new or unpublished data or relevant meeting abstracts. Figure 1. Study flow diagram. Study Selection The 4 criteria for analyzing studies in this research synthesis were randomized, controlled trials, or retrospective or prospective cohort studies with a control (concurrent or historical) group that allowed assessment of the rate of reactivation of hepatitis B after the start of chemotherapy with or without lamivudine therapy; a report of HBV reactivation, HBV-related hepatitis, acute hepatic failure due to HBV, or HBV-related death; a clear definition of the baseline population in terms of HBsAg positivity; and more than 5 participants per treatment group. Trials were excluded if relevant data could not be extracted. Case reports or series and studies that included posttransplantation patients or those with rheumatologic diseases or HIV were also excluded. The primary outcome measure of this research synthesis was reactivation of hepatitis B, defined as at least a 10-fold increase in serum HBV DNA levels with an accompanying increase in serum ALT compared with baseline. Secondary outcome measures included HBV-related hepatitis, defined as an increase in serum ALT that was 2 or more times greater than baseline levels and a 10-fold increase in serum HBV DNA levels; HBV-related hepatic failure, defined as elevated serum ALT level and prolonged prothrombin time or other evidence of coagulopathy with jaundice with or without encephalopathy after starting chemotherapy in patients who met criteria for HBV-related hepatitis; and HBV-related death, defined as death of a patient who had documented HBV reactivation that was reported by the authors as an HBV-related death and who had no other apparent cause of death. Data Extraction and Study Quality Two investigators independently screened titles and abstracts and extracted data from eligible studies. The independently identified articles that met the initial screening criteria were collectively reviewed in their entirety by these 2 investigators and were verified for the extracted data. Subsequently, 2 additional investigators confirmed whether eligible studies met the inclusion criteria and independently assessed the accuracy of data extraction. When necessary, conflict was resolved by consensus of all 4 investigators. The Appendix Table summarizes the methodological characteristics of the 14 studies eligible for this research synthesis. We considered randomized, controlled trials as high-quality evidence, prospective cohort studies with a concurrent control group as intermediate-quality evidence, and retrospective cohort studies and studies with a historical control group as low-quality evidence. Appendix Table. Methodological Characteristics of Clinical Trials Assessing the Efficacy of Preventive Lamivudine Data Synthesis and Statistical Analysis For each eligible study, relative risk (RR) and the exact 2-sided 95% CI were computed for the primary (HBV reactivation) and secondary (HBV-related hepatitis, HBV-related hepatic failure, and HBV-related death) outcomes by using StatXact PROCs (Cytel, Cambridge, Massachusetts). An RR less than 1.00 indicates risk reduction in the intervention group (lamivudine) over the control group (no or deferred lamivudine use). Graphics were created by using Comprehensive Meta Analysis Software (Biostat, Englewood, New Jersey). Because of the heterogeneity of patient populations, study designs, and other study methods, we considered it inappropriate to compute pooled estimates. Instead, we present study-specific estimates of effect and qualitatively describe the patterns of results overall. Role of the Funding Source This project was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the Clinical Center, National Institutes of Health. The funding sources had no role in conducting the study and have no potential conflicts of interest. Results Characteristics and Quality of Studies Fourteen studies met the specified criteria for assessment of HBV reactivation (Figure 1). Of these, 12 studies were conducted in East Asia (8, 13, 1523) and 1 each in Turkey (24) and Israel (25) (Table 1). All studies were in English except for 1 in Chinese (20). There were 2 randomized, controlled trials (8, 21); 8 prospective cohort studies (13, 15, 20, 2226), including 3 with concurrent control groups and 5 with historical control groups (13, 15, 22, 23, 26); and 4 retrospective cohort studies (1619) (Table 1). In addition, we identified 1 study (27) that compared lamivudine versus control in a similar patient population, but it did not report any of the outcomes of interest. The authors were contacted but did not provide further information, and thus we did not include the study. The Appendix Table describes the methodological characteristics and other quality indicators of the studies included in this review. The studies were generally small and did not consistently provide primary and secondary outcomes stratified by age, sex, ethnicity or race, baseline serum ALT levels, serum HBV DNA levels, or HBsAg status. On the other hand, patients included in both the treatment and the control groups were derived from similar patient populations at the same treatment center and received similar chemotherapeutic regimens. Furthermore, few patients