Prophylaxis against hepatitis B reactivation among patients with lymphoma receiving rituximab

Abstract

Hepatitis B virus (HBV) reactivation occurs commonly in patients with non-Hodgkin lymphoma, receiving rituximab-based therapeutic regimen. Guidelines from different organizations are not all in agreement with regard to screening and antiviral prophylaxis, given the limited evidence. Antiviral prophylaxis has been recommended for all HBV surface antigen-positive patients. Evidence for benefit from prophylaxis has recently been recognized among HBV surface antigen-negative/HBV core antibody-positive patients. Incidence of HBV reactivation varies in different geographical locations and the decision to start antiviral prophylaxis should consider local incidence data. Given the increased rates of rituximab-associated HBV reactivation and potentially fatal outcome, it is prudent that all patients who receive rituximab should be screened for HBV markers.

Keywords::

• hepatitis B
• lymphoma
• prophylaxis
• reactivation
• rituximab

Background

Rituximab, a chimeric mouse human anti-CD20 monoclonal antibody that is used with other agents for cytotoxic therapy for CD20⁺ lymphoma is associated with HBV reactivation, with an incidence ranging from 1.5 to 23.8% [1]. There is substantial evidence that rituximab improves outcome in diffuse large B-cell lymphoma and follicular lymphoma, and the drug is now considered first-line therapy in these cases and as maintenance in the latter. Also, despite the limited evidence, rituximab is commonly used as part of salvage therapy for diffuse large B-cell lymphoma. The drug has become an integral part of the ‘backbone’ for the treatment of non-Hodgkin lymphoma [2].

HBV reactivation occurs not infrequently among hepatitis B carriers with lymphoma receiving immunosuppressive agents and/or cancer chemotherapy. These patients are usually inactive carriers, but when reactivation does occur, the outcome may be fulminant hepatitis with occasional fatality [3]. Available data show a reduced incidence of HBV reactivation using prophylactic lamivudine in cancer patients receiving rituximab- or fludarabine-based chemotherapy [4].

Guidelines recommendations

In 2008, the CDC published guidelines on the evaluation and management of chronic HBV patients receiving immunosuppressive or cytotoxic medications, specifically recommending serologic testing (HBV surface antigen [HBsAg], HBV core antibody [anti-HBc] and anti-HBs) so that prophylaxis may be given under appropriate circumstances [5]. Table 1 summarizes the recommendations from three different organizations on HBV screening and prevention of reactivation on patients receiving or will receive cancer chemotherapy or immunosuppressive therapy [6–8]. The American Society for Cancer and Oncology released a provisional clinical opinion (PCO) that acknowledged the risk of reactivation of hepatitis B among patients with cancer and stressed that there was insufficient evidence on the degree of risk for HBV reactivation among different types of cancers and therapeutic regimens. It recommended that HBV screening (HBsAg and sometimes anti-HBc) be done based on each patient’s individual risk of being a hepatitis carrier and the planned cytotoxic and/or immunosuppressive treatment. Specifically, the PCO recommended patients undergoing hematopoietic cell transplantation and all rituximab recipients undergo hepatitis B screening. If diagnosed with chronic HBV infection, then those patients may be given antiviral therapy before and during chemotherapy or immunosuppressive therapy. The PCO did not provide specific recommendations for management, acknowledging the limited evidence available [6].

Table 1. Summary of recommendations on hepatitis B virus screening and prevention of reactivation in patients receiving cancer chemotherapy or immunosuppressive therapy: three organizations.

	AASLD	EASL	ASCO
Who to screen	All needing immunosuppressive therapy and high risk for HBV infection	All candidates for chemotherapy and immunosuppressive therapy (rituximab is particularly mentioned as with high risk for reactivation)	Not all (use clinical judgment);High risk for HBV and who will receive therapy, including HSCT and rituximab
Screening tests ^†	HBsAg, anti-HBc	HBsAg, anti-HBc;HBV DNA in HBsAg^+	HBsAg;Anti-HBc in some (use clinical judgment);No evidence for testing anti-HBs
For HBsAg^+ status	Antiviral prophylaxis	Test for HBV DNA;Preemptive therapy in HBV DNA^+	May be given antiviral prophylaxis
For HBsAg−/anti-HBc^+ status	Not enough information to support antivral prophylaxis; monitor and start prophylaxis if HBV DNA^+	Test for HBV DNA;HBV DNA^+ should be treated as HBsAg^+;HBV DNA− should be monitored every 1–3 months (LFTs and HBV DNA);HSCT patients should get prophylaxis;(Some say prophylaxis for all who get rituximab &/or combined chemotherapy in hematologic cancers)	Unclear clinical significance;Generally indicates resolved infection;Reactivation may occur with immunosuppressive therapy;May be false positivie
When to initiate antiviral prophylaxis	At the onset of chemotherapy	During chemotherapy and/or immunosuppressive therapy	May be given before starting and while on chemotherapy
Antiviral prophylaxis/pre-emptive therapy	Lamivudine or telbivudine for <12 months of chemotherapy;Tenofovir or entecavir if >12 months of therapy;Until 6 months after completing chemotherapy	Lamivudine if HBV DNA <2000 IU/ml and short-term chemotherapy;Entecavir or tenofovir if HBV DNA >2,000 IU/ml and multiple cycles of therapy	Hepatology or infectious diseases consultation

^†Cost–effectiveness is demonstrated for screening all lymphoma patients for HBsAg⁺ status.

AASLD: American Association for the Study of Liver Diseases; Anti-HBc: Antibody to hepatitis B core antigen; Anti-HBs: Antibody to hepatitis B surface antigen; ASCO: American Society of Clinical Oncology; EASL: European Association for the Study of the Liver; HBsAg: Hepatitis B surface antigen; HSCT: Hematopoietic stem cell transplant; LFTs: Liver function tests.

The European Association for the Study of the Liver and American Association for the Study of Liver Diseases (EASL and AASLD) have published clinical practice guidelines with similar recommendations regarding antiviral prophylaxis for patients with hepatitis B markers and undergoing chemotherapy/immunosuppression for malignancy. Differences in the recommendations, as noted, are minor [7,8].

Box 1 shows a list of patients/populations at high risk for hepatitis B, for whom screening/vaccination is recommended [5]. Universal agreement exists in checking high-risk patients for HBsAg initially, followed by additional testing and administration of antiviral prophylaxis for those who are HBsAg⁺. Controversial areas (mainly due to lack of data) include universal HBV screening, HBV markers to be tested during screening, type and duration of antiviral prophylaxis and most recently, the management of HBsAg−/anti-HBc⁺ patients.

Box 1. Patients and populations at high risk for hepatitis B for whom screening and/or vaccination are recommended.

• Born in areas with high-to-intermediate HBV endemicity (HBsAg⁺ prevalence ≥2%)

• US-born people with parents who were born in high endemicity regions (HBsAg⁺ prevalence ≥8%)

• Intravenous drug users

• Men who have sex with men

• Patients needing immunosuppressive therapy, including chemotherapy and immunosuppression related to organ or hematopoietic stem cell transplantation, and immunosuppressive therapies for rheumatologic and gastrointestinal disorders

• Patients with elevated liver function tests of unknown etiology

• Blood, plasma, organ, tissue or semen donors

• Hemodialysis patients

• Pregnant women (not specifically at high risk, but screening and vaccination are recommended)

• Born to HBsAg⁺ mothers

• Patients who share needles with persons who are HBsAg⁺

• Household or sexual contacts of persons who are HBsAg⁺

• Persons who are sources of contact of bodily fluids of patients who might need postexposure prophylaxis

• HIV⁺

• Hepatitis C-infected patients

HBV reactivation with & without antiviral prophylaxis in cancer patients on rituximab

Adherence to the practice of giving lamivudine for the prevention of rituximab-associated HBV reactivation was studied during 2009–2010 at our cancer center in Michigan [9]. Non-Hodgkin lymphoma was the main indication for therapy with rituximab. Among rituximab recipients, 15.9% were inadvertently not screened for HBV, and in those who were screened, only one patient (0.6%) was HBsAg⁺ and 11.5% were anti-HBc⁺. The patient with HBsAg⁺ (anti-HBc⁺ and HBV DNA−) status had reactivation (defined in this study as the reappearance of HBV DNA and elevated alanine aminotransferase [ALT]) while on lamivudine prophylaxis, and none among the HBsAg−/anti-HBc⁺ cancer patients had reactivation. The patient with HBV reactivation promptly improved with antiviral therapy. This suggests a low rate of HBV reactivation in our region.

Presently, there is no unified definition for HBV reactivation. The AASLD defined reactivation as the ‘reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B,’ which meant abrupt reappearance or rise of HBV DNA or the reappearance of HBsAg in patients with resolved hepatitis B. The EASL gave a similar definition, adding elevated ALT to HBV DNA >2000 IU/ml as the indicators of necroinflammation [7,8]. Some also included the reappearance of hepatitis B e antigen, which is another marker of active viral replication [1].

At our institution, we recommend lamivudine prophylaxis in all HBsAg⁺ patients at a daily dose of 100 mg orally starting 7 days before rituximab until at least 12 weeks after completing the course.

The AASLD and EASL guidelines agree that lamivudine prophylaxis should be given for chemotherapy of short duration, with AASLD defining ‘short’ as ≤12 months, while the antivirals recommended for those who receive longer duration of chemotherapy are entecavir and tenofovir. Both organizations are concerned regarding the high rate of resistance to lamivudine when the drug is used for long durations. On the other hand, entecavir and tenofovir are known to have the highest barrier to resistance emergence and so these drugs are recommended for long treatment durations. AASLD specifies that antiviral prophylaxis should be given until 6 months after the completion of chemotherapy [7,8].

HBsAg−/anti-HBc⁺ patients: new data

Previous reports estimated that rituximab-associated HBV reactivation can occur in as high as 8.9% of HBsAg−/anti-HBc⁺ patients [9]. In the recent randomized controlled trial from Taiwan, among HBsAg−/anti-HBc⁺ patients with lymphoma, the incidence of HBV reactivation in patients not receiving antiviral prophylaxis was 17.9% and reverse seroconversion (defined as the reappearance of HBsAg) was 10.3%. But with entecavir for prevention, the incidence of reactivation was just 2.4% (reactivation occurred in 1 patient; p = 0.027 vs controls), and there were no cases of reverse seroconversion [1]. The study showed a much higher rate of HBV reactivation in the nonprophylaxis group compared with a similar population in Michigan.

The Taiwan study noted that reactivation and reverse seroconversion occurred even in the HBsAg−/anti-HBc⁺ subpopulation, specifically in 1 out of 4 patients in the HBV DNA⁺ population, and more importantly, in 2 out of 10 patients in the HBV DNA− patients. Based on these data, the authors recommended that antiviral prophylaxis should be extended even to HBsAg−/anti-HBc⁺/HBV DNA− patients [1]. Despite having just 80 patients enrolled in their study, this randomized controlled trial concluded that in screening lymphoma patients for HBV, all markers including HBsAg, anti-HBc and anti-HBs (a predictor of HBV reactivation, if negative) should be requested, and antiviral prophylaxis should be considered if either of the first two tests are positive. If this recommendation were to be widely accepted, then a large number of patients with anti-HBc marker alone may be subjected to chemoprophylaxis.

The question of geographical location (or possibly, race), however, continues to be important since the above was a study from Asia, where the rates of reactivation seem to be high. A look at the available incidence rates of HBV reactivation in patients not on antiviral prophylaxis from different parts of the world reveal that in Hong Kong (in 2006), the incidence was 8% in patients receiving rituximab-based therapy, and even higher (12.2%) if steroids were added [10]. Similarly, another Asian study from Japan by Matsue et al. had a reactivation rate of 8% in the HBsAg−/anti-HBc⁺ population [11]. Closer to our rate in Michigan, a 2008 study from Italy reported a lower HBV reactivation incidence of 2.7% in lymphoma patients treated with an anti-CD20 monoclonal antibody and not receiving antiviral prophlyaxis [12].

The varying incidence rates of HBV reactivation among the published studies could also be due to the different definitions used. For example, the study by Targhetta, et al. defined HBV-related ‘liver disease’ as >threefold rise in ALT from baseline that exceeded the upper limit of normal, or an absolute ALT increase of >100 IU/ml, in contrast to HBV reactivation defined by the AASLD and/or EASL [12]. To accurately compare the incidence rates among studies, the definitions should be unified around the world and across different organizations.

The incidence rate of reactivation in patients with lymphoma, including those with HBsAg−/anti-HBc⁺ status, appears to vary in different geographical regions. In Asia, the incidence appears particularly high. In areas where the incidence is high, antiviral prophylaxis seems reasonable for lymphoma patients with only an anti-HBc⁺ test during treatment with rituximab. But in areas with low reactivation rates, the liberal administration of antiviral prophylaxis should await further prospective studies. Instead, as the European guidelines recommend, monitoring liver function tests closely (every 1–3 months while receiving rituximab) among patients with HBsAg−/anti-HBc⁺ status and performing HBV DNA test for any unexplained increase in liver function tests would be reasonable in order to identify HBV reactivation early and to initiate appropriate management.

In summary, all patients who are to receive rituximab as immunotherapy for lymphoma should be screened for HBV with HBsAg, anti-HBc and anti-HBs tests. Patients with anti-HBs− and anti-HBc− status may be offered the HBV vaccine, if appropriate. HBsAg⁺ lymphoma patients should be given antiviral prophylaxis. Type of drug may be based on the HBV DNA and length of immunotherapy. Duration of prophylaxis should be given for at least 3–6 months after completing therapy. Antiviral prophylaxis for those who are only anti-HBc⁺ should be considered for those residing in high HBV prevalence areas. In lower prevalence areas, close monitoring and HBV DNA surveillance where appropriate may be used as guides for management. While management of hepatitis B in patients with lymphoma is fairly well-characterized, more data are urgently needed on the frequency of HBV reactivation and its management in patients undergoing chemotherapy/immunosuppressive therapy for other malignancies.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus.