Hepatitis B After Rituximab in NHL
Hepatitis B After Rituximab in NHL
Abstract & Commentary
Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Hepatitis B virus (HBV) reactivation after rituximab or other immune suppressive therapies may lead to serious adverse outcomes. The authors retrospectively reviewed HBV serology of CD20 positive B-cell lymphoma without active HBV (i.e., negative HBsAg) before and after rituximab. Of the 230 tested, 56 (24%) were anti-HBc positive; the five cases of HBV reactivation all occurred in these 56 patients. Moreover, four of the five were anti-HBs negative (a.k.a, isolated anti-HBc). All received entacavir with the only HBV complication of transaminitis. None of the anti-HBc negative patients reactivated. Isolated anti-HBc, particularly lacking anti-HBs, may be at heightened risk of HBV reactivation after rituximab.
Source: Matsue K, et al. Reactivation of hepatitis B virus after rituximab-containing treatment of patients with CD20-positive B-cell lymphoma. Cancer. 2010. Jul. 1. [Epub ahead of print].
Increasingly, the risk of chronic hepatitis b virus (HBV) reactivation related to cancer treatment is becoming appreciated. HBV reactivation may lead to mild changes, such as transient transaminitis, or fatal complications, such as hepatic failure. Although the greatest risk appears to be found in patients with hepatitis B surface antigen positivity (indicated chronic active infection), some patients have serologic evidence of prior, but resolved, infection based on antibody to HBV core (anti-HBc) and/or antibody hepatitis B surface antigen (anti-HBsAg). Nevertheless, even in these patients, a low level of virus replication can be detected,1 and reactivation may occur, particularly after rituximab.2 The risk of HBV reactivation, particularly for HBsAg-negative patients, remains poorly characterized.
In this report, Matsue et al performed an observational study of 252 lymphoma patients receiving rituximab to characterize the risk of HBV reactivation among HBsAg-negative subjects. The median age was 70 years (range 15 to 93 years), and 62.5% had a diagnosis of diffuse large B-cell lymphoma (DLCL). Rituximab was administered as combination therapy with a variety of regimens, usually containing steroids. Hepatitis serology was either evaluated prior to treatment in real-time or on cryopreserved sera, although in 13 where serologic testing was performed later and inferred about the baseline status. There were 22 patients who did not have baseline testing and, thus, 230 had anti-HBc and anti-HBsAg results at baseline. Of these, 24.3% were anti-HBc positive. Among these 55 positive patients, 36/55 (65.4%) were anti-HBsAg positive and 19/55 (34.5%) were anti-HBsAg negative. Four patients negative for anti-HBc were positive for anti-HBsAg.
Overall, HBV reactivation, defined by a positive HBsAg (all were negative at baseline), occurred in 5/252 (2.0%). HBV reactivation occurred exclusively in patients harboring anti-HBc, for a reactivation rate of 5/56 (8.9%) in these patients. Of these anti-HBc patients, four of 19 lacking anti-HBs reactivated, compared to one of 37 anti-HBsAg positive patients. Of the five reactivating patients, all were started on anti-viral therapy and none had more serious HBV complications. Interestingly, nine patients were excluded from the study group, as they harbored HBsAg at baseline; they still received rituximab after empiric lamivudine or entecavir and no cases of severe hepatitis developed.
Commentary
Hepatitis B Virus (HBV) infection is a common infection worldwide. Acute infection is rarely fatal. Some people may develop chronic active infection, as evidenced by HBsAg, usually infants or young children. Even with resolved infection, however, HBV DNA may be detected.1 Chemotherapy and/or immunosuppression may pose a significant risk of HBV reactivation, most commonly reported among those harboring chronic active hepatitis (i.e., HBsAg positive) after immunosuppressive therapy. The risk of HBV reactivation, even among those harboring resolved infection (i.e., anti-HBc and/or anti-HBsAg), also has recently been appreciated after highly immunosuppressive therapy. Rituximab may be the prototypical drug for HBV reactivation the severe B-cell lymphopenia results in a proclivity toward opportunistic viral infections such as HBV.
Matsue et al evaluated consecutive adults admitted to a hospital in Japan who had received rituximab-based combination therapy. They found, among 252 HBsAg negative patients, that around 24% harbored anti-HBc, suggesting resolved HBV infection. HBV reactivation occurred in five patients, all among the 56 patients having anti-HBc at baseline, for a rate 8.9% in anti-HBc positive, HBsAg-negative patients. None of the anti-HBc-negative patients reactivated. Reactivation primarily occurred in those who also lacked anti-HBs (i.e, 4/19 or 21.1%). The data are quite similar to another series in Asia where Yeo et al reported five of 21 (23%) HBsAg-negative, anti-HBc positive patients after CHOP with rituximab reactivated HBV, compared to none of 25 with similar serology who did not receive rituximab.3 However, others reportedly have markedly lower rates of HBV reactivation.4 Of note, none of the patients who had HBV reactivation had serious liver complications, and all received anti-viral therapy after the diagnosis.
Continued controversy exists over the best screening and management for HBV in cancer patients. To the extent anti-viral prophylaxis may attenuate the course, and some cases may be fatal, the CDC recently recommended all patients undergoing chemotherapy or immunosuppressive treatment be screened for HBV (MMWR. vol 57, 2008). The American Society of Clinical Oncology (ASCO) recently responded that data for improved outcomes, based on screening and/or treatment, were lacking and, thus, suggested an individualized approach.5 Ultimately, ASCO recommended screening subjects with risk factors and those undergoing highly immunosuppressive therapy including, but not limited to, rituximab or stem cell transplantation. Interpreting this and other studies presents several challenges. First, the studies, as a rule, are observational, use varied definitions of HBV reactivation and, most importantly, derive from high-prevalence populations. The actual benefit of prophylaxis with anti-viral therapy remains unknown. For example, in this series, despite anti-viral prophylaxis being initiated only at diagnosis of HBV reactivation, no serious complications arose. Further, the type of chemotherapy treatment clearly impacts the course, with certain regimens carrying a much higher risk for clinical HBV reactivation. In a population at low risk for HBV exposure, some of the anti-HBc positive but negative for HBsAg and anti-HBsAg will likely be false-positive results.
Taken together, clinicians must be aware of HBV infection. At least for immunosuppressive regimens, such as rituximab and stem cell transplant, and those harboring risk factors for HBV exposure (e.g., country of birth, intravenous drug use, men having sex with men), a system to screen for HBV, and/or assess for risk factors, may be entertained. Screening inevitably will lead to the challenge of determining what serologic results, if any, should prompt anti-viral prophylaxis. Lastly, if unexplained hepatic complications emerge after chemotherapy, HBV reactivation should be entertained. In summary, patients with anti-HB core positivity but negative HBsAg and negative anti-HBsAg may be at risk of HBV reactivation after rituximab-based treatment. n
References
1. Rehermann B, et al. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2: 1104-1108.
2. Hui CK, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131:59-68.
3. Yeo W, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605-611.
4. Koo YX, et al. Risk of hepatitis B virus reactivation in patients who are hepatitis B surface antigen negative/antibody to hepatitis B core antigen positive and the role of routine antiviral prophylaxis. J Clin Oncol. 2009;27:2570-2571; author reply 2571-2572.
5. Artz AS, et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol. ;28:3199-3202.
Hepatitis B virus (HBV) reactivation after rituximab or other immune suppressive therapies may lead to serious adverse outcomes. The authors retrospectively reviewed HBV serology of CD20 positive B-cell lymphoma without active HBV (i.e., negative HBsAg) before and after rituximab. Of the 230 tested, 56 (24%) were anti-HBc positive; the five cases of HBV reactivation all occurred in these 56 patients. Moreover, four of the five were anti-HBs negative (a.k.a, isolated anti-HBc). All received entacavir with the only HBV complication of transaminitis. None of the anti-HBc negative patients reactivated. Isolated anti-HBc, particularly lacking anti-HBs, may be at heightened risk of HBV reactivation after rituximab.Subscribe Now for Access
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