Hepatitis B Re-activation with Rituximab TherapyKalliopi Zachou; George N. DalekosTargeted immune modulators, commonly referred to as biolog
Hepatitis B Re-activation with Rituximab Therapy
Targeted immune modulators, commonly referred to as biological response modifiers or 'biologics', are a relatively new category of medications used in the treatment of certain types of immunological, haematological/oncological and inflammatory diseases. In 1998, the US Food and Drug Administration (FDA) approved the first of the 'biologics' (infliximab) and since then several additional agents for the treatment of various rheumatic diseases, lymphoma and inflammatory bowel disease have been approved. Overall, these agents substantially improve the index disease and are generally safe for short-term treatment, although even now evidence is insufficient to reliably determine the comparative effectiveness and safety for many 'biologics' and to definitely assess the risk/benefit balance because sound long-term safety data are still missing.
Rituximab, a human/murine chimeric monoclonal antibody directed against the CD20 antigen expressed on the surface of normal and malignant B lymphocytes, was approved by the FDA in 2006 primarily for treating B-cell malignancies such as non-Hodgkin's lymphomas. Nowadays, its use has expanded either 'in-label' or 'off-label' to many diseases including rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, auto-immune haemolytic anaemia, pemphigus vulgaris, Sjogren's syndrome, graft vs. host disease, cryoglobulinaemia, multiple sclerosis, membranous nephropathy, auto-immune hepatitis and dermatomyositis.[3,4]
However, as with other immune modulators, the current label for rituximab contains a black box warning about the risk of serious infections leading to hospitalizations or death. Among these serious infections, a special concern about an increased risk of re-activation of hepatitis B virus (HBV) infection is also included, although the exact impact of rituximab on the incidence of HBV re-activation in patients with current or past HBV infection remains largely unknown.
There is no doubt that HBV infection can re-activate in the setting of immunosuppression or chemotherapy as demonstrated in several studies by the detection of elevated HBV-DNA levels and elevated aminotransferases in patients undergoing cytotoxic chemotherapy or treatment either with conventional immunosuppressives or with 'biologics'-based therapy.[5–8] Re-activation is usually subclinical but not infrequently can result in severe disease, including acute liver failure and death. Therefore, multiple liver societies (i.e. AASLD, APASL, EASL) have already published recommendations calling for universal screening for HBV infection with HBsAg for all patients undergoing immunosuppression or chemotherapy. In addition, pre-emptive antiviral prophylaxis for HBsAg-positive patients is currently recommended during and at least 6–12 months following the completion of immunosuppression,[9–12] because it has been shown that this strategy drastically reduces the re-activation rates of HBV.[6–8, 13]
At present, it is well known that the abovementioned risk of HBV re-activation is quite high among HBV carriers, particularly if rituximab is given alone or in combination with steroids.[11,14] The issue is much more complex in patients with serological markers of past HBV infection [HBsAg negative with positive antibodies against the HBV core antigen (anti-HBc positive)] undergoing either conventional chemotherapy or rituximab-based therapy. For instance, the EASL clinical practice guidelines for the management of chronic HBV infection in HBsAg-negative patients with positive anti-HBc antibodies who receive chemotherapy and/or immunosuppression suggest HBV-DNA determination in the serum and if undetectable, strict follow-up by means of ALT and HBV-DNA testing. Treatment with potent antivirals having a high barrier to resistance (i.e. entecavir or tenofovir) is recommended upon confirmation of HBV re-activation before ALT elevation. However, there is no clear evidence for when and how often this 'strict' follow-up should be performed because surrogate or prognostic markers related to the development of HBV re-activation in these subjects are obscure and the cost effectiveness particularly of HBV-DNA serial testing is unknown.
In this issue of the journal, two papers try to clarify this important topic.[15,16] In the first study, Méndez-Navarro et al.  assessed HBV serology screening in patients with non-Hodgkin's lymphoma starting rituximab-based chemotherapy in an attempt to address adherence rates to the general screening recommendations and also to determine the rates of HBV re-activation, antiviral prophylaxis among HBsAg-positive patients and the impact of this prophylaxis. In the second study, Watanabe et al.  assessed the incidence and clinical features associated with re-appearance of serum HBV-DNA in Japanese patients with past HBV infection who received rituximab-based therapy for haematological diseases.
Although both studies suffer from several limitations such as retrospective design, the small number of subjects and the different assays used for HBV-DNA determination (and thus not comparable cut-offs), they have resulted not only in very important but also in some ways worrisome findings that may have significant clinical implications.
Actually, in the US study, the authors found that only a third of patients undergoing rituximab-containing therapy had HBV serology performed or had documentation of serology performed outside their institution. Of note, they found that re-activation of HBV among those with known HBsAg positivity was not infrequent (50%; one developed acute liver failure and died). More surprisingly, only 37.5% of these HBsAg-positive carriers received prophylaxis, indicating that the lack of comprehensive screening and prophylaxis clearly impacted outcomes. These findings really raise major concerns regarding safety in the management of rituximab-treated patients as a whole and not as a single disease. If this is the case in a US tertiary centre, then the rates of HBV screening and prophylaxis could be even lower in community hospitals resulting potentially in significant harm to unscreened and unprophylaxed patients. Further support to the importance of HBV screening in candidates for rituximab-based therapy is revealed from the same study because 20% of the ALT flares during treatment were attributed directly to HBV re-activation in a region where HBV prevalence is not high. On the contrary, the authors did not observe a single re-activation in their group of 25 HBsAg-negative and known anti-HBc-positive patients undergoing rituximab therapy.
In the Japanese study, the incidence of re-appearance of HBV infection was evaluated during immunosuppressive treatment in patients with serological markers of past HBV infection. Contrary to the findings of the US study, it was found that significantly more patients undergoing rituximab-containing therapy for lymphoma experienced re-appearance of HBV infection (21% of patients) compared with none of those who received treatment regimens not containing anti-CD20 (P<0.05). However, the authors were not able to find any surrogate or prognostic marker that could predict HBV re-activation.
The issue of rituximab-based therapy and HBV re-activation among HBV carriers has been assessed recently by Pei et al.  and Evens et al.. In a retrospective study including 115 patients with B-cell lymphoma, 8 of 10 HBsAg-positive patients (80%) who received rituximab chemotherapy without prophylaxis experienced HBV-related hepatitis, which, as in most of the reported cases, had clinically severe characteristics. In a recent meta-analysis by Evens et al., the authors performed a comprehensive search of all not only published rituximab-related cases of HBV re-activation but also from the FDA Adverse Event Reporting System (AERS) MedWatch database. They identified 183 unique cases of rituximab-associated HBV re-activation from the literature (27 patients from case reports and 156 from case series) and 118 cases from FDA AERS. Similar to the findings of the present American study, the median time from last rituximab dose to re-activation was 3 months (range 0–12), although 29% occurred >6 months after the last dose. Within the FDA AERS data, there was a strong signal for rituximab-associated HBV re-activation [proportional reporting ratio=28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean=26.4, 95% CI 21.4–31.1].
There are at present three systematic analyses in the English literature on HBV re-activation among HBsAg-negative, anti-HBc-positive patients undergoing rituximab-based chemotherapy.[5,18,19] In accordance with the study of Watanabe et al., Hui et al.  reported a higher frequency of HBV re-activation in anti-HBc-positive patients who received rituximab-based treatment (16.3%) compared with those treated with conventional therapy like CHOP without rituximab (1%), while Yeo et al., in a prospective randomized trial of 104 anti-HBc-positive patients, found a rate of re-activation of 23.8% in patients treated with rituximab plus CHOP compared with 0% in patients treated only with CHOP. In parallel with the above two studies[18,19] and the present Japanese study in Liver International, the recent meta-analysis by Evens et al.  found that the anti-HBc-positive patients had a more than five-fold increased rate of rituximab-associated HBV re-activation compared with non-rituximab-treated patients. Why did the present American study fail to find similar results in anti-HBc-positive patients? Possible explanations include differences in study design, HBV genotypes, sample sizes, subject ethnicity, baseline HBV-DNA levels, diverse molecular techniques used for HBV-DNA detection and variable ALT cut-offs for the definition of hepatitis during treatment. Indeed, further support for the need of HBV-DNA testing at baseline in HBsAg-negative, anti-HBc-positive patients undergoing chemotherapy comes from a recent Italian study where this testing had a 28% predictive ability to forecast HBsAg seroconversion in HBV-DNA-positive patients, but more importantly a 90% ability to forecast persistent HBsAg negativity in HBV-DNA-negative patients.
In our opinion, three major issues emerge from the two articles in this issue. First, adherence to HBV screening and prophylaxis guidelines is suboptimal in patients undergoing therapy with rituximab-based regimens. This finding is of major concern because re-activation of hepatitis B is important not only because of its potentially fatal outcome but also because it can be effectively prevented with potent antivirals, and in the 21st century, it should be unacceptable for even one death that could be prevented.
Second, the abovementioned facts underline that guidelines regarding HBV screening and prophylaxis are not known or followed by all physicians and that further education of the involved parties about the hazards of HBV re-activation is absolutely necessary. The current use of rituximab has spread beyond the oncology/haematology area and therefore, international and local liver societies, particularly in HBV-endemic regions must educate other medical specialists in order to achieve the well-known Hippocratic aphorism to treat the patient as a human being and not as a disease. Perhaps, the increasing fragmentation and subspecialization of internal medicine, with the proliferation of highly specialized areas of expertise sometimes, may have detrimental results.
Third, the issue of antiviral prophylaxis of patients with serological markers of past HBV infection undergoing rituximab therapy remains unclear, but because the level of immunosuppression is critical for the risk of HBV re-activation[21,22] and this drug induces a very profound and long-lasting immunosuppression, which can result in severe, even fatal HBV re-activation, pre-emptive therapy with potent nucleos(t)ide analogues such as entecavir or tenofovir should be considered at least in patients with HBV-DNA serum positivity before treatment. For those difficult cases with negative serum HBV-DNA before treatment with rituximab-based therapy, strict adherence to the guidelines of the international liver societies, namely, close and careful monitoring of the patients is needed, although even one solid single surrogate prognostic marker for the re-appearance of HBV is not available.[9–11] Therefore, we still need somebody to define precisely the words 'close' and 'careful' in order to know how often and when should we investigate the patient with past HBV infection for one or all of ALT, HBV-DNA and HBsAg. Is there any candidate?