American Journal of Transplantation 2014; XX: 1–9 Wiley Periodicals Inc.
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12649
Personal Viewpoint
Hepatitis B Reactivation and Rituximab: A New Boxed Warning and Considerations for Solid Organ Transplantation S. T. Martin1,*, S. M. Cardwell1, M. D. Nailor1,2 and S. Gabardi3,4,5,6 1
Department of Pharmacy Services, Hartford Hospital, Hartford, CT 2 Department of Pharmacy Practice, University of Connecticut, Storrs, CT 3 Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, MA 4 Department of Transplant Surgery, Brigham and Women’s Hospital, Boston, MA 5 Renal Division, Brigham and Women’s Hospital, Boston, MA 6 Department of Medicine, Harvard Medical School, Boston, MA Corresponding author: Spencer T. Martin, [email protected]
Use of rituximab, a chimeric monoclonal antibody directed at the CD20 antigen, continues to increase in solid organ transplantation (SOT) for several off-label uses. In September 2013, the United States Food and Drug Administration (FDA) issued a Drug Safety Communication to oncology, rheumatology and pharmacy communities outlining a new Boxed Warning for rituximab. Citing 109 cases of fatal hepatitis B virus (HBV) reactivation in persons receiving rituximab therapy with previous or chronic HBV infection documented in their Adverse Event Reporting System (AERS), the FDA recommends screening for HBV serologies in all patients planned to receive rituximab and antiviral prophylaxis in any patient with a positive history of HBV infection. There is a lack of data pertaining to this topic in the SOT population despite an increase in off-label indications. Previous reports suggest patients receiving rituximab, on average, were administered six doses prior to HBV reactivation. Recommendations on prophylaxis, treatment and rechallenging patients with therapy after resolution of reactivation remain unclear. Based on data from the FDA AERS and multiple analyses in oncology, SOT providers utilizing rituximab should adhere to the FDA warnings and recommendations regarding HBV reactivation until further data are available in the SOT population. Keywords: Hepatitis B virus, immunosuppression, rituximab, solid organ transplantation
Abbreviations: AASLD, American Association for the Study of Liver Disease; AERS, Adverse Event Reporting System; AMR, antibody-mediated rejection; anti-HBc, antibody to the hepatitis B core antigen; anti-HBe, antibody to the hepatitis B e antigen; anti-HBs, antibody to the hepatitis B surface antigen; ASCO, American Society of Clinical Oncology; CDC, Centers for Disease Control; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; EASL, European Association for the Study of the Liver; FDA, United States Food and Drug Administration; HBcAb, hepatitis B core antibody; HBcAg, hepatitis B core antigen; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBIg, hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HLA, human leukocyte antigen; PTLD, posttransplant lymphoproliferative disorder; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SOT, solid organ transplantation Received 20 November 2013, revised 18 December 2013 and accepted for publication 30 December 2013
Introduction A member of the Hepadnavirus family, hepatitis B virus (HBV) is a double-stranded DNA virus with eight identified genotypes. Despite vaccination and improved screening and infection control techniques to reduce transmission, HBV remains widespread with an estimated 400 million people infected worldwide. In the United States, there are an estimated 600 000 to 1.25 million infected, although the rate of new infections has dropped dramatically (1). Globally, 620 000 people die each year from HBV-related liver disease. Compared to the general population, rates of infection are higher in hemodialysis and renal transplant populations due to the need for blood transfusions related to anemia, nosocomial contamination via dialysis machines or via donor transmission of a transplanted allograft (2). Infected patients are at increased risk of cirrhosis, decompensated liver failure and hepatocellular carcinoma. Rituximab, a cytolytic monoclonal human/murine chimeric antibody directed against the CD20 antigen of immature and mature B cells, was approved by the United States Food and Drug Administration (FDA) in November 1997 for the treatment of relapsed or refractory low-grade or 1
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follicular B cell non-Hodgkin’s lymphoma (3). Since that time, approved indications have increased to include chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. Off-label use of rituximab has expanded into solid organ transplantation (SOT), often as an adjunctive agent for its utility in mitigating the humoral allograft response. As a potent cytolytic agent, rituximab is associated with a variety of complications, including myelosuppression, cytokine release syndrome, infectious complications, severe skin reactions and anaphylactic reactions. Administration of rituximab has been linked to opportunistic infections such as cytomegalovirus reactivation, parvovirus B19 infection and varicella-zoster infection, but risk remains poorly defined (4–6). In September 2013, the FDA issued a Drug Safety Communication outlining a new Boxed Warning and recommendations to decrease the risk of HBV reactivation in patients with prior HBV infection receiving rituximab (7). Reactivation of HBV has been defined by the American Association for the Study of Liver Disease (AASLD) as the reappearance of active necroinflammatory disease of the liver in a person known to have the inactive hepatitis B surface antigen (HBsAg) carrier state or resolved HBV, or an abrupt reappearance or rise in HBV DNA in a patient with previously inactive or resolved HBV (8). Based on the approved indications for rituximab, the FDA communication plan was aimed at the oncology, rheumatology and pharmacy communities. Despite the potential risk, there is a significant lack of information regarding HBV reactivation in SOT recipients receiving rituximab. In this report, we aim to summarize pertinent data on the risk of HBV reactivation with rituximab, discuss its potential impact in SOT, and make recommendations on screening, prophylaxis and treatment of HBV reactivation.
Role of Rituximab in SOT The Fab domain of the rituximab antibody binds to the CD20 antigen, a nonglycosylated phosphoprotein transmembrane, resulting in profound B cell depletion. The rituximab mechanism of action for B cell depletion is multifaceted including complement-dependent killing, antibody-dependent cell-mediated cytotoxicity and activation of the apoptotic pathway (9). Reduction of B cells from the peripheral blood occurs within a few days of the first dose of rituximab administration, with complete B cell depletion occurring within 6 weeks of therapy. The role of rituximab in SOT has expanded in recent years, including treatment of antibodymediated rejection (AMR), posttransplant lymphoproliferative disorder (PTLD), acute rejection, and pretransplant conditioning for both ABO-incompatible donation and HLA desensitization protocols (9). Due in large part to the lack of randomized-controlled data and inconsistencies in practice, consensus on efficacy, 2
dosing and appropriate indications for rituximab in SOT remains ill-defined. Regardless, rituximab represents a significant addition to the small armamentarium of medications available in SOT with the potential to mitigate the humoral response and treat B cell lymphomas. With the administration in SOT considered ‘‘off-label,’’ postmarket requirements and FDA communications do not specifically target the transplant community. However, this patient population might be at significant risk for reactivation of HBV and transplant practitioners’ awareness of this potential risk is imperative.
HBV Etiology and Pathophysiology HBV is a partially double-stranded DNA virus with a lipoprotein envelope enclosing a nucleocapsid core. The viral component of the envelope is primarily composed of HBsAg. The major protein component of the viral core is hepatitis B core antigen (HBcAg). DNA replication produces both complete virions and HBsAg subviral filamentous or spherical protein particles. Titers of complete virions range from 104 to 109/mL, whereas subviral proteins attain titers of 1013/mL. Detection of both virions and subviral particles of circulating HBsAg is the primary method of identification of HBV disease (10). HBV DNA encodes only four genes: the surface antigen or capsule encoding the viral envelope, the e antigen and nucleocapsid core to enclose the viral DNA, the polymerase protein, and the viral X protein. The polymerase protein facilitates replication of viral DNA via an RNA intermediary, and the viral X protein modifies viral and host cell signaling and gene expression. HBV selectively infects hepatocytes, although viral DNA has been isolated in nonhepatic tissues (11). Initial entry into hepatocytes begins with binding of the viral envelope to the host cell by an unknown receptor-mediated mechanism. The viral core is then transported to the nucleus, where viral DNA is permanently incorporated into the host cell, allowing for transcription via host cell RNA polymerase and establishing lifelong infection. Viral RNA is then transported to the cytoplasm, where the surface, core, polymerase and viral X protein are translated. Virion assembly occurs in the cytoplasm with the encapsulation of viral RNA in a nucleocapsid core, after which viral DNA is synthesized by reverse transcription. Some viral cores are maintained within the host cell, but the majority exit as complete virions after envelopment via budding from portions of the host cell membrane where HBsAg envelope proteins are bound. Viral replication is not directly toxic to host cells, as evidenced by the presence of a chronic, asymptomatic carrier state of HBV infection. Host immune response is thought to be primarily responsible for hepatocellular inflammation and injury in HBV infection. A strong host T cell response has been observed in patients with acute, self-limiting HBV. Also in these patients, a correlation has American Journal of Transplantation 2014; XX: 1–9
HBV Reactivation With Rituximab
been observed between levels of cytotoxic T cells and alanine aminotransferase, suggesting that host cytotoxic T cells may be involved in hepatocellular injury (12). In patients with chronic HBV, levels of HBsAg and viral DNA are markedly lower than are present in initial infection. If initial host T cell response is insufficient to resolve the infection, a chronic but incomplete immune response may explain the reduced levels of circulating virus and antigen, as well as the cumulative hepatocellular damage of chronic disease. It should be emphasized that although seroconversion and clearance of circulating virus can occur, viral DNA is permanently incorporated into host cells and all exposed patients are at risk of disease reactivation with immune escape (Figure 1).
HBV Serology HBV is initially identified by the presence of HBsAg or viral DNA in the blood, after an incubation period of 4–10 weeks from infection. Hepatitis B e antigen (HBeAg) may also be detected in early infection, and its detection is associated with continually elevated viral titers during chronic infection. Seroconversion of HBeAg to antibody to the hepatitis B e antigen (anti-HBe) occurs at a rate of 5–10% annually in adults with chronic infection, corresponding with a transient rise in alanine aminotransferase and a significant decrease in HBV viremia as HBeAg titers resolve. Antibody to the hepatitis B core antigen (anti-HBc) is the earliest antibody to develop, approximately 6–8 weeks after infection. The presence of IgM anti-HBc is indicative of acute infection; conversion to IgG anti-HBc indicates chronic infection. Antibody to the hepatitis B surface antigen (anti-HBs) is generally indicative of recovery and subsequent immunity to HBV. Patients who have been successfully immunized will be positive for serum anti-HBs at a titer of at least 10 mIU/mL; the presence of both antiHBs and anti-HBc is indicative of previous infection and
subsequent immunity after seroconversion and clearance of the virus (Table 1).
HBV in Transplantation Donation Due to the continued disparity between available organs for donation and the number of patients awaiting transplantation, the use of allografts from anti-HBc[þ] donors has gained favor as a high-risk donation, especially in recipients previously vaccinated against HBV or with prior HBV infection. Hepatocytes are the primary site for HBV infection and replication; therefore, the risk of transmission of HBV to a recipient is highest in liver transplantation. The advent of both hepatitis B immunoglobulin (HBIg) and potent HBV-antiviral agents has improved prophylactic and treatment strategies, increasing interest in the utilization of anti-HBc[þ] donors. Despite primarily hepatocyte infection, recipients of renal and cardiothoracic transplantation are also at risk for HBV infection due to extra-hepatic circulation of HBV. The utilization of these organs varies from center to center, as do protocols for prophylaxis and treatment of recipients posttransplant.
Recipient outcomes HBV viral replication is enhanced in the presence of immunosuppression, potentially leading to progressive liver failure in the form of cirrhosis or hepatocellular carcinoma. The impact of HBV infection on SOT has not yet been clearly elucidated. However, an increased risk of allograft loss and patient mortality has been described in the renal transplant population (13). Historically, the risk of HBV reinfection after liver transplantation from an anti-HBc[þ] donor was nearly 100% (14). The resulting increase in viral
Figure 1: Immune phases of hepatitis B infection. Chronic HBV infection can be broadly divided into four immunologic phases: immune tolerance, immune clearance, immune control and immune escape. After a period of viral replication with little inflammation, a strong host immune response corresponds with loss of HBeAg and conversion to an inactive carrier state. Immune escape is characterized by HBV reactivation with flares of viremia and inflammation, potentially augmented by immune modulating therapy. During both immune clearance and immune escape, fluctuations in HBV DNA and ALT can be observed. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. þIncreased risk of cirrhosis.
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3
Martin et al Table 1: Hepatitis B serologies and interpretations HBsAg þ þ
Anti-HBs
Anti-HBc
HBeAg
HBV DNA
þ þ
þ þ þ þ
þ
þ þ þ
Interpretation 1
Susceptible Chronic infection, immune controlled2 Prior vaccination; immune Occult infection2,3 Active infection; low-level viremia2,3 Active infection; high-level viremia2,3
anti-HBe, antibody to the hepatitis B e antigen; anti-HBs, antibody to the hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. 1 Patients should receive HBV vaccination prior to immune modulating therapy. 2 At risk of reactivation. 3 Requires treatment of active disease prior to immune modulating therapy.
replication rates in the setting of immunosuppression leads to an accelerated progression of liver disease and a poor prognosis overall. With the introduction of new anti-HBV therapies, the rate of HBV reinfection after anti-HBc[þ] donation in liver transplantation has been reduced to 5–10% with similar survival rates compared to standard organ donation (15).
Hepatitis B Reactivation After Rituximab Administration The first reported case of rituximab-associated HBV reactivation was described by Dervite et al in 2001 (16). Since that time, there have been multiple analyses attempting to determine the risk of HBV reactivation after rituximab therapy, most often in patients treated for B cell lymphoma (17–19). In a single-center, retrospective analysis, Yeo et al (20) reported on 46 patients that were antiHBsAg[]/anti-HBc[þ] with CD20 positive diffuse large B cell lymphoma prior to initiating rituximab therapy. Of those patients, 25 received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and 21 were administered rituximab þ CHOP (R-CHOP). No patients in the CHOP group experienced HBV reactivation compared to five (23.8%) in the R-CHOP group (p ¼ 0.0148). A more recent, multinational (East Asia), retrospective review examined 340 patients who were HBsAg[]/hepatitis B core antibody (HBcAb)[þ] (n ¼ 178) or HBsAg[þ] (n ¼ 162) receiving R-CHOP (n ¼ 307) or rituximab, cyclophosphamide, vincristine and prednisone (n ¼ 210) (21). HBV reactivation occurred in 17 (9.6%) and 45 (27.8%) of HBsAg[]/HBcAb[þ] and HBsAg[þ] patients, respectively. However, a secondary, prospective, cross-sectional analysis from the same data set found that only 2.4% of patients experienced HBV reactivation in HBsAg[]/HBcAb[þ] group (n ¼ 83), while a similar incidence of 27.2% was noted in the patients with HBsAg[þ] (n ¼ 44) prior to therapy (21). A review of 183 HBV reactivation cases (case reports, n ¼ 27; case series, n ¼ 156) related to rituximab administration found that the median number of doses received 4
prior to HBV reactivation was six (range, 3–10) with a median time of 3 months from the last dose (range, 0–12) at the time of diagnosis (22). Of the 156 case series, only 5 included a nonrituximab comparison; however, HBV reactivation was statistically more likely to occur in patients receiving rituximab (20/244, 8.2%) compared to those who did not (3/453, 0.6%; p < 0.0001). Of the total 183 cases identified in the literature, 166 (90.7%) were outside of the United States. These data are not surprising considering that the United States accounts for approximately 0.31% of the worldwide HBV-infected population. An additional 118 cases from the FDA Adverse Event Reporting System (AERS) database were identified over a 12-year period (November 1997 to September 2009) (22). Of these additional 118 cases, 54 (45.8%) were outside of the United States. The mortality rate among the AERS cases was 58.4%. However, the FDA AERS cases were found to be statistically less complete than reports found in the literature (p < 0.0001). The above data describes risk in chronically infected as well as in patients whose infection was believed to have been considered resolved. It is also important to note that most patients who were receiving rituximab were also receiving other immunosuppressive chemotherapies and the contribution of those other therapies, if any, remains unknown. Patients undergoing SOT who receive rituximab are receiving other immunosuppressive therapies, but their contribution to reactivation is also unknown.
New Boxed Warning In September 2013, the FDA released a Drug Safety Communication for rituximab and ofatumumab, a second monoclonal antibody with activity against the CD20 antigen, describing the addition of HBV reactivation resulting in ‘‘fulminant hepatitis, hepatic failure and death’’ as a Boxed Warning for both medications (7). The new warning suggests that the potential for HBV reactivation is most concerning in patients who are actively infected, HBsAg[þ], HBsAg[]/anti-HBc[þ] or have a resolved HBV infection (HBsAg[], anti-HBc[þ] and hepatitis B surface antibody [HBsAb][þ]). The warning is the result of 109 American Journal of Transplantation 2014; XX: 1–9
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cases (rituximab, n ¼ 106; ofatumumab, n ¼ 3) of fatal hepatitis B–related acute liver injury identified in the FDA AERS database. The analysis includes any related report from the time rituximab was introduced to the market in November 1997 until August 2012. Only 32 cases were considered to have sufficient information to meet criteria for HBV reactivation. Of the 32 patients, 22 (68.6%) experienced HBsAg seroconversion from negative to positive with a history of HBV or anti-HBc[þ]. The remaining 10 patients were HBsAg[þ] prior to initiating therapy and found to have an increased HBV viral load afterward. Of the 32 patients, antiviral prophylaxis and antiviral treatment for HBV reactivation were administered in 3 (9.4%) and 9 (28.1%) patients, respectively. The onset of HBV reactivation was found to range from 63 days to 12 months after the last dose of therapy. All 32 patients were noted to be treated with additional chemotherapeutic agents aside from rituximab. The remaining 77 patients identified in the AERS database were not considered to have enough information to meet criteria for HBV reactivation: 36 (46.8%) had insufficient documentation of screening; 25 (32.5%) reported only partial information on screening; and the remaining 16 (20.8%) cases could not be distinguished between primary HBV or reactivation, or were from invalidated literature reports.
Proposed Mechanisms The mechanism of rituximab-associated HBV reactivation is not well understood. Immediate B cell depletion may disrupt CD8þ cytotoxic T cell killing of HBV-infected hepatocytes by diminishing B cell, antigen-presenting properties (23). Rituximab administration has also been shown to impact T cell immunity by increasing Th1/Th2 and Tc1/Tc2 ratios and promoting up-regulation of Fas ligand on Th1 and Th2 cells; however, the effect on HBV reactivation, if any, remains unknown (24). Finally, it has been speculated that reactivation in the setting of rituximab therapy may be dependent on mutations in the major antigenic S region of certain HBV strains (25). More specifically, five mutations, L110R, R122K, Y/F134S, P142L and D144A, are considered capable of ‘‘escaping’’ patient anti-HBsAb, and may be responsible for persistent, low levels of HBV replication despite positive serologies for immunity. The Y/F134S, P142L and D144A mutations have also been associated with HBV vaccination failure, further supporting the potential for certain HBV strains to elude host-immunity (26). It is theorized that these mutant escape strains are generally nonpathogenic, unless patients are subjected to intense immunosuppression, such as rituximab therapy.
Screening Previously, the Centers for Disease Control (CDC) recommended that anyone receiving cytotoxic or immunosuppressive therapy, including patients receiving chemotherapy or American Journal of Transplantation 2014; XX: 1–9
immunosuppression for malignancy, SOT, and rheumatologic or gastroenterologic disorders, be screened for HBV infection (27). In 2010, the American Society of Clinical Oncology (ASCO) issued a Provisional Clinical Opinion on the topic and suggested that HBV screening required clinical judgment, but should be considered in patients at high risk for chronic HBV or those requiring an intensive immunosuppressive regimen, including rituximab (28). The FDA Drug Safety Communication, in addition to the new Box Warning, includes recommendations for screening prior to, during and after rituximab therapy. In contrast to the CDC and ASCO recommendations, the FDA suggests that all patients, not just those deemed high-risk, be screened for HBsAg and anti-HBc before beginning rituximab. Reactivation has been described during therapy and upward of 12 months after cessation. Therefore, the FDA recommends that patients be monitored for clinical and laboratory signs of HBV infection or reactivation throughout the administration of rituximab and in the months afterward.
Prophylaxis and Treatment The FDA Drug Safety Communication recommends that if pretreatment screening results in evidence of prior infection (HBsAg[þ] or HBsAg[]/anti-HBc[þ]), a plan for monitoring and HBV antiviral prophylaxis should be developed with the assistance of a hepatitis expert (7). Unfortunately, there is no guidance on preferred antiviral agents or length of therapy for prophylaxis. In the event of HBV reactivation in patients receiving rituximab, it is recommended to immediately discontinue the drug and start appropriate treatment for HBV. The statement also recommends discontinuation of any additional chemotherapy the patient may be receiving until the HBV infection is controlled or resolved. As stated above, the FDA communication is directed toward specialty areas of practice, and the ability to decrease or stop immunosuppressive agents in SOT is likely impossible. Although it is generally recommended that immunosuppressive therapy be reduced in patients with life-threatening opportunistic infections, ongoing immunosuppressive therapy should be individualized. Insufficient evidence exists regarding recommendations for the resumption of rituximab posttreatment of HBV reactivation. The AASLD guidelines recommend that prophylactic antiviral therapy be administered to hepatitis B carriers at the onset of therapy with rituximab and maintained for 6 months after discontinuation. However, the optimal length of treatment remains unclear, as late-onset HBV reactivation has been reported despite 12 months of prophylactic therapy after completion of rituximab (8,29). In contrast to the AASLD guidelines, the European Association for the Study of the Liver (EASL) clinical practice guidelines for management of hepatitis B suggest that HBV carriers be administered prophylaxis throughout 5
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chemotherapeutic or immunosuppressive therapy and for 12 months after completion (30). The EASL recommendations do attempt to address monitoring and dosing concerns in the SOT recipient, but do not specifically address rituximab and fail to comment on the life-long requirement of immunosuppressive therapy in SOT, suggesting a need for better understanding and future study in this population. Lamivudine, a nucleoside reverse transcriptase inhibitor, has the most evidence for use as HBV reactivation prophylaxis in patients receiving rituximab (Table 2) (19,20,31–35). Several other medications with activity against HBV are available: nucleotide reverse transcriptase inhibitors adefovir and tenofovir, and nucleoside reverse transcriptase inhibitors entecavir and telbivudine. Dosing for available agents can be found in Table 3. Lamivudine is well tolerated and cost-effective, but development of resistance is well documented in both prophylaxis and treatment (32,36). High rates of resistance with telbivudine, resulting in additional resistance to lamivudine, limit the use of telbivudine overall. In patients who develop lamivudine resistance, higher-dose entecavir, adefovir and tenofovir retain activity. Cross-resistance has
been documented between adefovir and tenofovir, making entecavir the agent of choice for HBV resistance to either drug. Tenofovir is the logical choice to treat entecavirresistant HBV, as there is generally little cross-resistance, but clinical data are lacking (8). It should be noted that breakthrough HBV reactivation has been documented in patients receiving prophylaxis with entecavir, but data regarding tenofovir prophylaxis are unavailable (34). Adefovir was listed as a second-line agent in the 2009 update of the AASLD guidelines for the treatment of chronic HBV after it was demonstrated to be less effective than tenofovir in the treatment of active disease. Additionally, nephrotoxicity has been reported in approximately 3% of patients on chronic therapy with adefovir. The potential for nephrotoxicity is also listed for tenofovir in these guidelines; however, an analysis of outcomes in 227 patients treated chronically with tenofovir, entecavir and lamivudine found no difference in adverse drug events with any agent (37). Lamivudine is a reasonable choice for prophylaxis; it is the most studied to date, and multiple other agents may be used for treatment if breakthrough with resistant virus occurs. All patients at risk of HBV reactivation should receive prophylaxis with an appropriate agent at the onset of
Table 2: Summary of Prophylactic Regimens for HBV Reactivation for Rituximab Therapy Study (reference)
n
HBV serology criteria for inclusion
Tsutsumi et al1 (19)
25
Data unavailable
Retrospective
Lamivudine 100 mg, variable duration
0/10 on PPX 4/15 (27%) no PPX
Yeo et al1 (20)
24
HBsAg[þ] ¼ 24
Retrospective
Lamivudine 100 mg prior to and for at least 8 weeks post
2/15 (13%) on PPX 2/15 (13%) post withdrawal of PPX 2/9 (22%) no PPX
He et al (31)
29
HBsAg[þ] ¼ 29; HBeAg[þ] ¼ 8; HBeAg[] ¼ 21
Prospective, nonrandomized
Lamivudine 100 mg 1 week prior and at least 2 months post
0/29 (0%) on PPX 1/29 (3%) post withdrawal of PPX
Chen et al (32)
50
HBsAg[þ] ¼ 50
Prospective, nonrandomized
Lamivudine 100 mg 1 week prior, at least 3 months post
4/30 (13%) on PPX 12/20 (60%) no PPX
Huang et al (33)
80
HBsAg[] and HBcAb[þ] ¼ 80; HBsAb[þ] ¼ 58
Randomized, controlled
Entecavir 0.5 mg 1 week prior, at least 3 months post vs. entecavir 0.5 mg/day at onset of reactivation
1/41 (2%) on PPX 7/39 (18%) no PPX
Kim et al (34)
24
HBsAg[þ] ¼ 24; HBeAg[þ] ¼ 14; HBeAg[] ¼ 10
Retrospective
Lamivudine 100 mg prior to and throughout chemotherapy
1/24 (4%) on PPX 1/24 (4%) post withdrawal of PPX
HBsAg[þ] ¼ 118; HBeAb[þ] ¼ 39; HBcAb[þ] ¼ 121
Retrospective, nonrandomized comparison
Lamivudine 100 mg vs. entecavir 0.5 mg 1 week prior, at least 6 months post
18/89 (20%) on lamivudine 4/34 (12%) on entecavir
Li et al (35)
123
Design
Prophylactic agent
HBV reactivation
HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PPX, antiviral prophylaxis. 1 Patients receiving prophylaxis are a subset of a larger analysis.
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HBV Reactivation With Rituximab Table 3: Therapeutic options for hepatitis B virus prophylaxis and treatment postrituximab administration Drug
Dose1
Need for renal dosing adjustments
Considerations
Cost
Yes; CrCl < 50 mL/min Yes; CrCl < 50 mL/min
Slow onset of antiviral activity Also appropriate for use as treatment in patients with active disease
$42.11 per 10 mg tablet $41.59 per 0.5 mg or 1 mg tablets
Lamivudine3
1 mg once daily (treatment or lamivudine-refractory) 100 mg once daily (prophylaxis)
Yes; CrCl < 50 mL/min
$16.12 per 100 mg tablet
Telbivudine3,4
600 mg once daily (treatment)
Yes; CrCl < 50 mL/min
Tenofovir
300 mg once daily (treatment)
Yes; CrCl < 50 mL/min
Generally well tolerated, most experience, potential for resistance with long-term prophylaxis Low genetic barrier to resistance Also appropriate for use as treatment in patients with active disease
Adefovir2 Entecavir
10 mg once daily (treatment) 0.5 mg once daily (prophylaxis or treatment na€ıve)
$35.47 per 600 mg tablet $33.29 per 300 mg tablet
1
Specific recommendations on length of prophylactic therapy cannot be made at this time due to lack of data. Begin at onset of rituximab and continue for at least 6 months postrituximab therapy; reactivations have been reported for upward of 12 months after therapy with rituximab. 2 Incidence of elevated serum creatinine has been observed to be as high as 51% in liver transplant patients, likely due to concomitant use of other potentially nephrotoxic medications, baseline renal insufficiency and predisposing comorbidities. 3 Nonpreferred medication for treatment of active disease. 4 Potential for cross-resistance with lamivudine.
immune modulating therapy. Patients with active disease should receive treatment with tenofovir, entecavir or a combination of both. No data are available to support a role for HBIg in prevention or treatment of HBV reactivation in patients receiving rituximab at this time.
Considerations in SOT The utility of the FDA AERS database for identifying potential safety risks is apparent; however, the scarcity of high-quality data cited by the FDA for rituximab-induced HBV reactivation is concerning. It is important to note that the FDA’s recommendations are based solely on fatal HBV reactivation, highlighting the seriousness of this outcome. Defining risk factors and capturing the true prevalence of rituximab-associated HBV reactivation are essential in developing the most effective strategies for avoidance. Unfortunately, the FDA warning and the currently available data fall short of providing guidance for prophylaxis and management of at-risk patients. Furthermore, the validity of the AERS data remains in question due to potential reporting bias, incomplete data and underreporting. Regardless of impact outside of the scope of approved use, it seems the FDA and pharmaceutical industry will continue to focus their analyses and communication efforts solely on those healthcare professionals practicing within the approved indication of a medication. In the current regulatory environment, off-label use of medications in SOT will remain a mainstay of practice; therefore, it is critical that practitioners within SOT communicate with each other and American Journal of Transplantation 2014; XX: 1–9
with colleagues utilizing similar or shared medications in other specialties. Risk of HBV reactivation in the setting of standard immunosuppression for SOT patients is estimated to be approximately 5% (38). Reactivation in the setting of rituximab therapy in this population is limited to case reports, with no data available on SOT recipients who have received an allograft from an HBV positive donor (39,40). One major difference seen in the data previously discussed above was that patients received, on average, six doses of rituximab prior to HBV reactivation (22). Except for management of PTLD, rituximab is generally given as a single dose in SOT population, although subsequent doses may be required on a case-by-case basis or when required by center-specific protocols for treatment of AMR and desensitization. Due to lack of data, the appropriateness of reintroducing rituximab therapy in patients who have experienced rituximab-associated HBV reactivation remains in question. Finally, regarding additional risk factors for HBV reactivation in the setting of rituximab use, there are no available data on the potential impact of commonly administered immunosuppressive medications in the SOT population. Future study in this area is warranted, specifically in the setting of aggressive immunosuppressive protocols for desensitization prior to transplantation or the treatment of active rejection. The lack of systematic data for rituximab-associated HBV reactivation in the SOT population is disquieting. Although direct-acting antiviral HBV therapies are relatively safe, not 7
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knowing the true risk of HBV reactivation makes initial judgments on the use of prophylactic strategies difficult. Further, the efficacy of prophylactic strategies including preferred agent, dosing and length of therapy remains unclear. Careful multicenter retrospective evaluations should be able to elucidate reactivation rates among SOT patients, as has been done in oncology patient populations. Prospective evaluations, utilizing historical controls, could then begin to describe the effectiveness of prophylactic regimens. Until that time, the use of rituximab in SOT will likely become more widespread for a variety of immunologic indications; the FDA recommendation for universal screening in all patients considered for therapy should be embraced by the SOT community. Routine screening for HBsAg, anti-HBc and anti-HBs is already engrained in the current culture of evaluating patients prior to transplantation or donation. Because HBV infection can occur posttransplantation, these same principles and systems that ensure patient safety prior to transplant must be adopted into our posttransplant care, especially when considering the use of potent immunosuppressive medications such as rituximab. We recommend that those patients with HBsAg[þ] or HBsAg[]/anti-HBc[þ] be administered antiviral prophylaxis immediately prior to the initiation of rituximab and upward of 6 months after the cessation of therapy. Vaccination to HBV prior to transplantation remains the most efficacious and costeffective strategy to preventing HBV infection in the SOT population.
8. 9.
10. 11.
12.
13.
14. 15. 16.
17.
18.
Disclosure 19.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. 20.
References 1. Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009; 50: 661–662. 2. Degos F, Lugassy C, Degott C, et al. Hepatitis B virus and hepatitis B-related viral infection in renal transplant recipients. A prospective study of 90 patients. Gastroenterology 1988; 94: 151–156. 3. Rituxan (rituximab) package insert. South San Francisco, CA: Genentech, Inc., 2013, September. 4. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001; 345: 1000. 5. Sharma VR, Fleming DR, Slone SP. Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab. Blood 2000; 96: 1184–1186. 6. Bermu´dez A, Marco F, Conde E, Mazo E, Recio M, Zubizarreta A. Fatal visceral varicella-zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 2000; 85: 894–895. 7. Arzerra (ofatumumab) and Rituxan (rituximab): Drug safety warning—New boxed warning, recommendations to decrease risk of hepatitis B reactivation. US Food and Drug Administration
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2013. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm369846. htm. Accessed November 20, 2013. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: 507–539. Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: History and mechanism of action. Am J Transplant 2006; 6: 859–866. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med 2004; 350: 1118–1129. Mason A, Theal J, Bain V, Adams E, Perillo R. Hepatitis B virus replication in damaged endothelial tissues of patients with extrahepatic disease. Am J Gastroenterol 2005; 100: 972–976. Sprengers D, van der Molen RG, Kusters JG, et al. Analysis of intrahepatic HBV-specific cytotoxic T-cells during and after acute HBV infection in humans. J Hepatol 2006; 45: 182–189. Kliem V, Burg M, Haller H, et al. Relationship of hepatitis B or C virus prevalence, risk factors, and outcomes in renal transplant recipients: Analysis of German data. Transplant Proc 2008; 40: 909–914. Fishman J, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751. Coffin CS, Terrault NA. Management of hepatitis B in liver transplant recipients. J Viral Hepat 2007; 14 (Suppl 1): 37–44. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Engl J Med 2001; 344: 68–69. Dong HJ, Ni LN, Sheng GF, Song HL, Xu JZ, Ling Y. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: A meta-analysis. J Clin Virol 2013; 57: 209–214. Matsue K, Kimura S, Takanashi Y, Iwama K, Fujiwara H, Yamakura M. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer 2010; 116: 4769–4776. Tsutsumi Y, Shigematsu A, Hashino S, et al. Analysis of reactivation of hepatitis B virus in the treatment of B cell nonHodgkin’s lymphoma in Hokkaido. Ann Hematol 2009; 88: 375– 377. Yeo W, Chan TC, Leung NW, 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. Kim SJ, Hsu C, Song YQ, et al. Hepatitis B virus reactivation in Bcell lymphoma patients treated with rituximab: Analysis from the Asia Lymphoma Study Group. Eur J Cancer 2013; 49: 3486–3496. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative disease: Meta-analysis and examination of FDA safety reports. Ann Oncol 2011; 22: 1170–1180. Lazdina U, Alheim M, Nystro¨m J, et al. Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent. J Gen Virol 2003; 84: 139–146. Stasi R, Del Poeta G, Stipa E, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007; 110: 2924–2930. Westhoff TH, Jochimsen F, Schmittel A, et al. Fatal hepatitis B reactivation by an escape mutant following rituximab therapy. Blood 2003; 102: 1930. Nainan OV, Kristova ML, Byan K, et al. Genetic variation of hepatitis B surface antigen coding region among infants with chronic hepatitis B virus infection. J Med Virol 2002; 68: 319–327.
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HBV Reactivation With Rituximab 27. Weinbaum CM, Williams I, Mast EE, et al. Recommendation for the identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep 2008; 57: 1–20. 28. Artz AS, Somerfield MR, Feld JJ, 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 disease. J Clin Oncol 2010; 28: 3199– 3202. 29. Chew E, Thursky K, Seymour JF. Very late onset hepatitis-B virus reactivation following rituximab despite lamivudine prophylaxis: The need for continued vigilance. Leuk Lymphoma 2013; doi: 10.3109/10428194.2013.813502 [Epub ahead of print]. 30. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol 2009; 50: 227–242. 31. He YF, Li YH, Wang FH, et al. The effectiveness of lamivudine in preventing hepatitis B viral reactivation in rituximab-containing regimen for lymphoma. Ann Hematol 2008; 87: 481–485. 32. Chen XQ, Peng JW, Lin GN, Li M, Xia ZJ. The effect of prophylactic lamivudine on hepatitis B virus reactivation in HBsAg-positive patients with diffuse large B-cell lymphoma undergoing prolonged rituximab therapy. Med Oncol 2012; 29: 1237–1241. 33. Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus
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reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 2013; 31: 2765–2772. Kim JS, Hahn JS, Park SY, et al. Long term outcome after prophylactic lamivudine treatment on hepatitis B virus reactivation in Non-Hodgkin’s Lymphoma. Yonsei Med J 2007; 48: 78–79. Li HR, Huang JJ, Guo HQ, et al. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J Viral Hepat 2011; 18: 877–883. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999; 30: 1302–1306. Ko¨klu¨ S, Tuna Y, Gu¨ls¸en MT, et al. Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol 2013; 11: 88–94. Blanpain C, Knoop C, Delforge ML, et al. Reactivation of hepatitis B after transplantation in patient with pre-existing anti-hepatitis B surface antigen antibodies: Report on three cases and review of the literature. Transplantation 1998; 66: 883–886. Fylaktou A, Daoudaki M, Dimou V, et al. Hepatitis B reactivation in a renal transplant patient due to a surface antigen mutant strain: A case report. Transplant Proc 2012; 44: 2773–2775. Gossmann J, Scheuermann EH, Kachel HG, Geiger H, Hauser IA. Reactivation of hepatitis B two years after rituximab therapy in a renal transplant patient with recurrent focal segmental glomerulosclerosis: A note of caution. Clin Transplant 2009; 23: 431–434.
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Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12649
Personal Viewpoint
Hepatitis B Reactivation and Rituximab: A New Boxed Warning and Considerations for Solid Organ Transplantation S. T. Martin1,*, S. M. Cardwell1, M. D. Nailor1,2 and S. Gabardi3,4,5,6 1
Department of Pharmacy Services, Hartford Hospital, Hartford, CT 2 Department of Pharmacy Practice, University of Connecticut, Storrs, CT 3 Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, MA 4 Department of Transplant Surgery, Brigham and Women’s Hospital, Boston, MA 5 Renal Division, Brigham and Women’s Hospital, Boston, MA 6 Department of Medicine, Harvard Medical School, Boston, MA Corresponding author: Spencer T. Martin, [email protected]
Use of rituximab, a chimeric monoclonal antibody directed at the CD20 antigen, continues to increase in solid organ transplantation (SOT) for several off-label uses. In September 2013, the United States Food and Drug Administration (FDA) issued a Drug Safety Communication to oncology, rheumatology and pharmacy communities outlining a new Boxed Warning for rituximab. Citing 109 cases of fatal hepatitis B virus (HBV) reactivation in persons receiving rituximab therapy with previous or chronic HBV infection documented in their Adverse Event Reporting System (AERS), the FDA recommends screening for HBV serologies in all patients planned to receive rituximab and antiviral prophylaxis in any patient with a positive history of HBV infection. There is a lack of data pertaining to this topic in the SOT population despite an increase in off-label indications. Previous reports suggest patients receiving rituximab, on average, were administered six doses prior to HBV reactivation. Recommendations on prophylaxis, treatment and rechallenging patients with therapy after resolution of reactivation remain unclear. Based on data from the FDA AERS and multiple analyses in oncology, SOT providers utilizing rituximab should adhere to the FDA warnings and recommendations regarding HBV reactivation until further data are available in the SOT population. Keywords: Hepatitis B virus, immunosuppression, rituximab, solid organ transplantation
Abbreviations: AASLD, American Association for the Study of Liver Disease; AERS, Adverse Event Reporting System; AMR, antibody-mediated rejection; anti-HBc, antibody to the hepatitis B core antigen; anti-HBe, antibody to the hepatitis B e antigen; anti-HBs, antibody to the hepatitis B surface antigen; ASCO, American Society of Clinical Oncology; CDC, Centers for Disease Control; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; EASL, European Association for the Study of the Liver; FDA, United States Food and Drug Administration; HBcAb, hepatitis B core antibody; HBcAg, hepatitis B core antigen; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBIg, hepatitis B immunoglobulin; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HLA, human leukocyte antigen; PTLD, posttransplant lymphoproliferative disorder; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SOT, solid organ transplantation Received 20 November 2013, revised 18 December 2013 and accepted for publication 30 December 2013
Introduction A member of the Hepadnavirus family, hepatitis B virus (HBV) is a double-stranded DNA virus with eight identified genotypes. Despite vaccination and improved screening and infection control techniques to reduce transmission, HBV remains widespread with an estimated 400 million people infected worldwide. In the United States, there are an estimated 600 000 to 1.25 million infected, although the rate of new infections has dropped dramatically (1). Globally, 620 000 people die each year from HBV-related liver disease. Compared to the general population, rates of infection are higher in hemodialysis and renal transplant populations due to the need for blood transfusions related to anemia, nosocomial contamination via dialysis machines or via donor transmission of a transplanted allograft (2). Infected patients are at increased risk of cirrhosis, decompensated liver failure and hepatocellular carcinoma. Rituximab, a cytolytic monoclonal human/murine chimeric antibody directed against the CD20 antigen of immature and mature B cells, was approved by the United States Food and Drug Administration (FDA) in November 1997 for the treatment of relapsed or refractory low-grade or 1
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follicular B cell non-Hodgkin’s lymphoma (3). Since that time, approved indications have increased to include chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. Off-label use of rituximab has expanded into solid organ transplantation (SOT), often as an adjunctive agent for its utility in mitigating the humoral allograft response. As a potent cytolytic agent, rituximab is associated with a variety of complications, including myelosuppression, cytokine release syndrome, infectious complications, severe skin reactions and anaphylactic reactions. Administration of rituximab has been linked to opportunistic infections such as cytomegalovirus reactivation, parvovirus B19 infection and varicella-zoster infection, but risk remains poorly defined (4–6). In September 2013, the FDA issued a Drug Safety Communication outlining a new Boxed Warning and recommendations to decrease the risk of HBV reactivation in patients with prior HBV infection receiving rituximab (7). Reactivation of HBV has been defined by the American Association for the Study of Liver Disease (AASLD) as the reappearance of active necroinflammatory disease of the liver in a person known to have the inactive hepatitis B surface antigen (HBsAg) carrier state or resolved HBV, or an abrupt reappearance or rise in HBV DNA in a patient with previously inactive or resolved HBV (8). Based on the approved indications for rituximab, the FDA communication plan was aimed at the oncology, rheumatology and pharmacy communities. Despite the potential risk, there is a significant lack of information regarding HBV reactivation in SOT recipients receiving rituximab. In this report, we aim to summarize pertinent data on the risk of HBV reactivation with rituximab, discuss its potential impact in SOT, and make recommendations on screening, prophylaxis and treatment of HBV reactivation.
Role of Rituximab in SOT The Fab domain of the rituximab antibody binds to the CD20 antigen, a nonglycosylated phosphoprotein transmembrane, resulting in profound B cell depletion. The rituximab mechanism of action for B cell depletion is multifaceted including complement-dependent killing, antibody-dependent cell-mediated cytotoxicity and activation of the apoptotic pathway (9). Reduction of B cells from the peripheral blood occurs within a few days of the first dose of rituximab administration, with complete B cell depletion occurring within 6 weeks of therapy. The role of rituximab in SOT has expanded in recent years, including treatment of antibodymediated rejection (AMR), posttransplant lymphoproliferative disorder (PTLD), acute rejection, and pretransplant conditioning for both ABO-incompatible donation and HLA desensitization protocols (9). Due in large part to the lack of randomized-controlled data and inconsistencies in practice, consensus on efficacy, 2
dosing and appropriate indications for rituximab in SOT remains ill-defined. Regardless, rituximab represents a significant addition to the small armamentarium of medications available in SOT with the potential to mitigate the humoral response and treat B cell lymphomas. With the administration in SOT considered ‘‘off-label,’’ postmarket requirements and FDA communications do not specifically target the transplant community. However, this patient population might be at significant risk for reactivation of HBV and transplant practitioners’ awareness of this potential risk is imperative.
HBV Etiology and Pathophysiology HBV is a partially double-stranded DNA virus with a lipoprotein envelope enclosing a nucleocapsid core. The viral component of the envelope is primarily composed of HBsAg. The major protein component of the viral core is hepatitis B core antigen (HBcAg). DNA replication produces both complete virions and HBsAg subviral filamentous or spherical protein particles. Titers of complete virions range from 104 to 109/mL, whereas subviral proteins attain titers of 1013/mL. Detection of both virions and subviral particles of circulating HBsAg is the primary method of identification of HBV disease (10). HBV DNA encodes only four genes: the surface antigen or capsule encoding the viral envelope, the e antigen and nucleocapsid core to enclose the viral DNA, the polymerase protein, and the viral X protein. The polymerase protein facilitates replication of viral DNA via an RNA intermediary, and the viral X protein modifies viral and host cell signaling and gene expression. HBV selectively infects hepatocytes, although viral DNA has been isolated in nonhepatic tissues (11). Initial entry into hepatocytes begins with binding of the viral envelope to the host cell by an unknown receptor-mediated mechanism. The viral core is then transported to the nucleus, where viral DNA is permanently incorporated into the host cell, allowing for transcription via host cell RNA polymerase and establishing lifelong infection. Viral RNA is then transported to the cytoplasm, where the surface, core, polymerase and viral X protein are translated. Virion assembly occurs in the cytoplasm with the encapsulation of viral RNA in a nucleocapsid core, after which viral DNA is synthesized by reverse transcription. Some viral cores are maintained within the host cell, but the majority exit as complete virions after envelopment via budding from portions of the host cell membrane where HBsAg envelope proteins are bound. Viral replication is not directly toxic to host cells, as evidenced by the presence of a chronic, asymptomatic carrier state of HBV infection. Host immune response is thought to be primarily responsible for hepatocellular inflammation and injury in HBV infection. A strong host T cell response has been observed in patients with acute, self-limiting HBV. Also in these patients, a correlation has American Journal of Transplantation 2014; XX: 1–9
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been observed between levels of cytotoxic T cells and alanine aminotransferase, suggesting that host cytotoxic T cells may be involved in hepatocellular injury (12). In patients with chronic HBV, levels of HBsAg and viral DNA are markedly lower than are present in initial infection. If initial host T cell response is insufficient to resolve the infection, a chronic but incomplete immune response may explain the reduced levels of circulating virus and antigen, as well as the cumulative hepatocellular damage of chronic disease. It should be emphasized that although seroconversion and clearance of circulating virus can occur, viral DNA is permanently incorporated into host cells and all exposed patients are at risk of disease reactivation with immune escape (Figure 1).
HBV Serology HBV is initially identified by the presence of HBsAg or viral DNA in the blood, after an incubation period of 4–10 weeks from infection. Hepatitis B e antigen (HBeAg) may also be detected in early infection, and its detection is associated with continually elevated viral titers during chronic infection. Seroconversion of HBeAg to antibody to the hepatitis B e antigen (anti-HBe) occurs at a rate of 5–10% annually in adults with chronic infection, corresponding with a transient rise in alanine aminotransferase and a significant decrease in HBV viremia as HBeAg titers resolve. Antibody to the hepatitis B core antigen (anti-HBc) is the earliest antibody to develop, approximately 6–8 weeks after infection. The presence of IgM anti-HBc is indicative of acute infection; conversion to IgG anti-HBc indicates chronic infection. Antibody to the hepatitis B surface antigen (anti-HBs) is generally indicative of recovery and subsequent immunity to HBV. Patients who have been successfully immunized will be positive for serum anti-HBs at a titer of at least 10 mIU/mL; the presence of both antiHBs and anti-HBc is indicative of previous infection and
subsequent immunity after seroconversion and clearance of the virus (Table 1).
HBV in Transplantation Donation Due to the continued disparity between available organs for donation and the number of patients awaiting transplantation, the use of allografts from anti-HBc[þ] donors has gained favor as a high-risk donation, especially in recipients previously vaccinated against HBV or with prior HBV infection. Hepatocytes are the primary site for HBV infection and replication; therefore, the risk of transmission of HBV to a recipient is highest in liver transplantation. The advent of both hepatitis B immunoglobulin (HBIg) and potent HBV-antiviral agents has improved prophylactic and treatment strategies, increasing interest in the utilization of anti-HBc[þ] donors. Despite primarily hepatocyte infection, recipients of renal and cardiothoracic transplantation are also at risk for HBV infection due to extra-hepatic circulation of HBV. The utilization of these organs varies from center to center, as do protocols for prophylaxis and treatment of recipients posttransplant.
Recipient outcomes HBV viral replication is enhanced in the presence of immunosuppression, potentially leading to progressive liver failure in the form of cirrhosis or hepatocellular carcinoma. The impact of HBV infection on SOT has not yet been clearly elucidated. However, an increased risk of allograft loss and patient mortality has been described in the renal transplant population (13). Historically, the risk of HBV reinfection after liver transplantation from an anti-HBc[þ] donor was nearly 100% (14). The resulting increase in viral
Figure 1: Immune phases of hepatitis B infection. Chronic HBV infection can be broadly divided into four immunologic phases: immune tolerance, immune clearance, immune control and immune escape. After a period of viral replication with little inflammation, a strong host immune response corresponds with loss of HBeAg and conversion to an inactive carrier state. Immune escape is characterized by HBV reactivation with flares of viremia and inflammation, potentially augmented by immune modulating therapy. During both immune clearance and immune escape, fluctuations in HBV DNA and ALT can be observed. ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. þIncreased risk of cirrhosis.
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3
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Anti-HBs
Anti-HBc
HBeAg
HBV DNA
þ þ
þ þ þ þ
þ
þ þ þ
Interpretation 1
Susceptible Chronic infection, immune controlled2 Prior vaccination; immune Occult infection2,3 Active infection; low-level viremia2,3 Active infection; high-level viremia2,3
anti-HBe, antibody to the hepatitis B e antigen; anti-HBs, antibody to the hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. 1 Patients should receive HBV vaccination prior to immune modulating therapy. 2 At risk of reactivation. 3 Requires treatment of active disease prior to immune modulating therapy.
replication rates in the setting of immunosuppression leads to an accelerated progression of liver disease and a poor prognosis overall. With the introduction of new anti-HBV therapies, the rate of HBV reinfection after anti-HBc[þ] donation in liver transplantation has been reduced to 5–10% with similar survival rates compared to standard organ donation (15).
Hepatitis B Reactivation After Rituximab Administration The first reported case of rituximab-associated HBV reactivation was described by Dervite et al in 2001 (16). Since that time, there have been multiple analyses attempting to determine the risk of HBV reactivation after rituximab therapy, most often in patients treated for B cell lymphoma (17–19). In a single-center, retrospective analysis, Yeo et al (20) reported on 46 patients that were antiHBsAg[]/anti-HBc[þ] with CD20 positive diffuse large B cell lymphoma prior to initiating rituximab therapy. Of those patients, 25 received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and 21 were administered rituximab þ CHOP (R-CHOP). No patients in the CHOP group experienced HBV reactivation compared to five (23.8%) in the R-CHOP group (p ¼ 0.0148). A more recent, multinational (East Asia), retrospective review examined 340 patients who were HBsAg[]/hepatitis B core antibody (HBcAb)[þ] (n ¼ 178) or HBsAg[þ] (n ¼ 162) receiving R-CHOP (n ¼ 307) or rituximab, cyclophosphamide, vincristine and prednisone (n ¼ 210) (21). HBV reactivation occurred in 17 (9.6%) and 45 (27.8%) of HBsAg[]/HBcAb[þ] and HBsAg[þ] patients, respectively. However, a secondary, prospective, cross-sectional analysis from the same data set found that only 2.4% of patients experienced HBV reactivation in HBsAg[]/HBcAb[þ] group (n ¼ 83), while a similar incidence of 27.2% was noted in the patients with HBsAg[þ] (n ¼ 44) prior to therapy (21). A review of 183 HBV reactivation cases (case reports, n ¼ 27; case series, n ¼ 156) related to rituximab administration found that the median number of doses received 4
prior to HBV reactivation was six (range, 3–10) with a median time of 3 months from the last dose (range, 0–12) at the time of diagnosis (22). Of the 156 case series, only 5 included a nonrituximab comparison; however, HBV reactivation was statistically more likely to occur in patients receiving rituximab (20/244, 8.2%) compared to those who did not (3/453, 0.6%; p < 0.0001). Of the total 183 cases identified in the literature, 166 (90.7%) were outside of the United States. These data are not surprising considering that the United States accounts for approximately 0.31% of the worldwide HBV-infected population. An additional 118 cases from the FDA Adverse Event Reporting System (AERS) database were identified over a 12-year period (November 1997 to September 2009) (22). Of these additional 118 cases, 54 (45.8%) were outside of the United States. The mortality rate among the AERS cases was 58.4%. However, the FDA AERS cases were found to be statistically less complete than reports found in the literature (p < 0.0001). The above data describes risk in chronically infected as well as in patients whose infection was believed to have been considered resolved. It is also important to note that most patients who were receiving rituximab were also receiving other immunosuppressive chemotherapies and the contribution of those other therapies, if any, remains unknown. Patients undergoing SOT who receive rituximab are receiving other immunosuppressive therapies, but their contribution to reactivation is also unknown.
New Boxed Warning In September 2013, the FDA released a Drug Safety Communication for rituximab and ofatumumab, a second monoclonal antibody with activity against the CD20 antigen, describing the addition of HBV reactivation resulting in ‘‘fulminant hepatitis, hepatic failure and death’’ as a Boxed Warning for both medications (7). The new warning suggests that the potential for HBV reactivation is most concerning in patients who are actively infected, HBsAg[þ], HBsAg[]/anti-HBc[þ] or have a resolved HBV infection (HBsAg[], anti-HBc[þ] and hepatitis B surface antibody [HBsAb][þ]). The warning is the result of 109 American Journal of Transplantation 2014; XX: 1–9
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cases (rituximab, n ¼ 106; ofatumumab, n ¼ 3) of fatal hepatitis B–related acute liver injury identified in the FDA AERS database. The analysis includes any related report from the time rituximab was introduced to the market in November 1997 until August 2012. Only 32 cases were considered to have sufficient information to meet criteria for HBV reactivation. Of the 32 patients, 22 (68.6%) experienced HBsAg seroconversion from negative to positive with a history of HBV or anti-HBc[þ]. The remaining 10 patients were HBsAg[þ] prior to initiating therapy and found to have an increased HBV viral load afterward. Of the 32 patients, antiviral prophylaxis and antiviral treatment for HBV reactivation were administered in 3 (9.4%) and 9 (28.1%) patients, respectively. The onset of HBV reactivation was found to range from 63 days to 12 months after the last dose of therapy. All 32 patients were noted to be treated with additional chemotherapeutic agents aside from rituximab. The remaining 77 patients identified in the AERS database were not considered to have enough information to meet criteria for HBV reactivation: 36 (46.8%) had insufficient documentation of screening; 25 (32.5%) reported only partial information on screening; and the remaining 16 (20.8%) cases could not be distinguished between primary HBV or reactivation, or were from invalidated literature reports.
Proposed Mechanisms The mechanism of rituximab-associated HBV reactivation is not well understood. Immediate B cell depletion may disrupt CD8þ cytotoxic T cell killing of HBV-infected hepatocytes by diminishing B cell, antigen-presenting properties (23). Rituximab administration has also been shown to impact T cell immunity by increasing Th1/Th2 and Tc1/Tc2 ratios and promoting up-regulation of Fas ligand on Th1 and Th2 cells; however, the effect on HBV reactivation, if any, remains unknown (24). Finally, it has been speculated that reactivation in the setting of rituximab therapy may be dependent on mutations in the major antigenic S region of certain HBV strains (25). More specifically, five mutations, L110R, R122K, Y/F134S, P142L and D144A, are considered capable of ‘‘escaping’’ patient anti-HBsAb, and may be responsible for persistent, low levels of HBV replication despite positive serologies for immunity. The Y/F134S, P142L and D144A mutations have also been associated with HBV vaccination failure, further supporting the potential for certain HBV strains to elude host-immunity (26). It is theorized that these mutant escape strains are generally nonpathogenic, unless patients are subjected to intense immunosuppression, such as rituximab therapy.
Screening Previously, the Centers for Disease Control (CDC) recommended that anyone receiving cytotoxic or immunosuppressive therapy, including patients receiving chemotherapy or American Journal of Transplantation 2014; XX: 1–9
immunosuppression for malignancy, SOT, and rheumatologic or gastroenterologic disorders, be screened for HBV infection (27). In 2010, the American Society of Clinical Oncology (ASCO) issued a Provisional Clinical Opinion on the topic and suggested that HBV screening required clinical judgment, but should be considered in patients at high risk for chronic HBV or those requiring an intensive immunosuppressive regimen, including rituximab (28). The FDA Drug Safety Communication, in addition to the new Box Warning, includes recommendations for screening prior to, during and after rituximab therapy. In contrast to the CDC and ASCO recommendations, the FDA suggests that all patients, not just those deemed high-risk, be screened for HBsAg and anti-HBc before beginning rituximab. Reactivation has been described during therapy and upward of 12 months after cessation. Therefore, the FDA recommends that patients be monitored for clinical and laboratory signs of HBV infection or reactivation throughout the administration of rituximab and in the months afterward.
Prophylaxis and Treatment The FDA Drug Safety Communication recommends that if pretreatment screening results in evidence of prior infection (HBsAg[þ] or HBsAg[]/anti-HBc[þ]), a plan for monitoring and HBV antiviral prophylaxis should be developed with the assistance of a hepatitis expert (7). Unfortunately, there is no guidance on preferred antiviral agents or length of therapy for prophylaxis. In the event of HBV reactivation in patients receiving rituximab, it is recommended to immediately discontinue the drug and start appropriate treatment for HBV. The statement also recommends discontinuation of any additional chemotherapy the patient may be receiving until the HBV infection is controlled or resolved. As stated above, the FDA communication is directed toward specialty areas of practice, and the ability to decrease or stop immunosuppressive agents in SOT is likely impossible. Although it is generally recommended that immunosuppressive therapy be reduced in patients with life-threatening opportunistic infections, ongoing immunosuppressive therapy should be individualized. Insufficient evidence exists regarding recommendations for the resumption of rituximab posttreatment of HBV reactivation. The AASLD guidelines recommend that prophylactic antiviral therapy be administered to hepatitis B carriers at the onset of therapy with rituximab and maintained for 6 months after discontinuation. However, the optimal length of treatment remains unclear, as late-onset HBV reactivation has been reported despite 12 months of prophylactic therapy after completion of rituximab (8,29). In contrast to the AASLD guidelines, the European Association for the Study of the Liver (EASL) clinical practice guidelines for management of hepatitis B suggest that HBV carriers be administered prophylaxis throughout 5
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chemotherapeutic or immunosuppressive therapy and for 12 months after completion (30). The EASL recommendations do attempt to address monitoring and dosing concerns in the SOT recipient, but do not specifically address rituximab and fail to comment on the life-long requirement of immunosuppressive therapy in SOT, suggesting a need for better understanding and future study in this population. Lamivudine, a nucleoside reverse transcriptase inhibitor, has the most evidence for use as HBV reactivation prophylaxis in patients receiving rituximab (Table 2) (19,20,31–35). Several other medications with activity against HBV are available: nucleotide reverse transcriptase inhibitors adefovir and tenofovir, and nucleoside reverse transcriptase inhibitors entecavir and telbivudine. Dosing for available agents can be found in Table 3. Lamivudine is well tolerated and cost-effective, but development of resistance is well documented in both prophylaxis and treatment (32,36). High rates of resistance with telbivudine, resulting in additional resistance to lamivudine, limit the use of telbivudine overall. In patients who develop lamivudine resistance, higher-dose entecavir, adefovir and tenofovir retain activity. Cross-resistance has
been documented between adefovir and tenofovir, making entecavir the agent of choice for HBV resistance to either drug. Tenofovir is the logical choice to treat entecavirresistant HBV, as there is generally little cross-resistance, but clinical data are lacking (8). It should be noted that breakthrough HBV reactivation has been documented in patients receiving prophylaxis with entecavir, but data regarding tenofovir prophylaxis are unavailable (34). Adefovir was listed as a second-line agent in the 2009 update of the AASLD guidelines for the treatment of chronic HBV after it was demonstrated to be less effective than tenofovir in the treatment of active disease. Additionally, nephrotoxicity has been reported in approximately 3% of patients on chronic therapy with adefovir. The potential for nephrotoxicity is also listed for tenofovir in these guidelines; however, an analysis of outcomes in 227 patients treated chronically with tenofovir, entecavir and lamivudine found no difference in adverse drug events with any agent (37). Lamivudine is a reasonable choice for prophylaxis; it is the most studied to date, and multiple other agents may be used for treatment if breakthrough with resistant virus occurs. All patients at risk of HBV reactivation should receive prophylaxis with an appropriate agent at the onset of
Table 2: Summary of Prophylactic Regimens for HBV Reactivation for Rituximab Therapy Study (reference)
n
HBV serology criteria for inclusion
Tsutsumi et al1 (19)
25
Data unavailable
Retrospective
Lamivudine 100 mg, variable duration
0/10 on PPX 4/15 (27%) no PPX
Yeo et al1 (20)
24
HBsAg[þ] ¼ 24
Retrospective
Lamivudine 100 mg prior to and for at least 8 weeks post
2/15 (13%) on PPX 2/15 (13%) post withdrawal of PPX 2/9 (22%) no PPX
He et al (31)
29
HBsAg[þ] ¼ 29; HBeAg[þ] ¼ 8; HBeAg[] ¼ 21
Prospective, nonrandomized
Lamivudine 100 mg 1 week prior and at least 2 months post
0/29 (0%) on PPX 1/29 (3%) post withdrawal of PPX
Chen et al (32)
50
HBsAg[þ] ¼ 50
Prospective, nonrandomized
Lamivudine 100 mg 1 week prior, at least 3 months post
4/30 (13%) on PPX 12/20 (60%) no PPX
Huang et al (33)
80
HBsAg[] and HBcAb[þ] ¼ 80; HBsAb[þ] ¼ 58
Randomized, controlled
Entecavir 0.5 mg 1 week prior, at least 3 months post vs. entecavir 0.5 mg/day at onset of reactivation
1/41 (2%) on PPX 7/39 (18%) no PPX
Kim et al (34)
24
HBsAg[þ] ¼ 24; HBeAg[þ] ¼ 14; HBeAg[] ¼ 10
Retrospective
Lamivudine 100 mg prior to and throughout chemotherapy
1/24 (4%) on PPX 1/24 (4%) post withdrawal of PPX
HBsAg[þ] ¼ 118; HBeAb[þ] ¼ 39; HBcAb[þ] ¼ 121
Retrospective, nonrandomized comparison
Lamivudine 100 mg vs. entecavir 0.5 mg 1 week prior, at least 6 months post
18/89 (20%) on lamivudine 4/34 (12%) on entecavir
Li et al (35)
123
Design
Prophylactic agent
HBV reactivation
HBcAb, hepatitis B core antibody; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PPX, antiviral prophylaxis. 1 Patients receiving prophylaxis are a subset of a larger analysis.
6
American Journal of Transplantation 2014; XX: 1–9
HBV Reactivation With Rituximab Table 3: Therapeutic options for hepatitis B virus prophylaxis and treatment postrituximab administration Drug
Dose1
Need for renal dosing adjustments
Considerations
Cost
Yes; CrCl < 50 mL/min Yes; CrCl < 50 mL/min
Slow onset of antiviral activity Also appropriate for use as treatment in patients with active disease
$42.11 per 10 mg tablet $41.59 per 0.5 mg or 1 mg tablets
Lamivudine3
1 mg once daily (treatment or lamivudine-refractory) 100 mg once daily (prophylaxis)
Yes; CrCl < 50 mL/min
$16.12 per 100 mg tablet
Telbivudine3,4
600 mg once daily (treatment)
Yes; CrCl < 50 mL/min
Tenofovir
300 mg once daily (treatment)
Yes; CrCl < 50 mL/min
Generally well tolerated, most experience, potential for resistance with long-term prophylaxis Low genetic barrier to resistance Also appropriate for use as treatment in patients with active disease
Adefovir2 Entecavir
10 mg once daily (treatment) 0.5 mg once daily (prophylaxis or treatment na€ıve)
$35.47 per 600 mg tablet $33.29 per 300 mg tablet
1
Specific recommendations on length of prophylactic therapy cannot be made at this time due to lack of data. Begin at onset of rituximab and continue for at least 6 months postrituximab therapy; reactivations have been reported for upward of 12 months after therapy with rituximab. 2 Incidence of elevated serum creatinine has been observed to be as high as 51% in liver transplant patients, likely due to concomitant use of other potentially nephrotoxic medications, baseline renal insufficiency and predisposing comorbidities. 3 Nonpreferred medication for treatment of active disease. 4 Potential for cross-resistance with lamivudine.
immune modulating therapy. Patients with active disease should receive treatment with tenofovir, entecavir or a combination of both. No data are available to support a role for HBIg in prevention or treatment of HBV reactivation in patients receiving rituximab at this time.
Considerations in SOT The utility of the FDA AERS database for identifying potential safety risks is apparent; however, the scarcity of high-quality data cited by the FDA for rituximab-induced HBV reactivation is concerning. It is important to note that the FDA’s recommendations are based solely on fatal HBV reactivation, highlighting the seriousness of this outcome. Defining risk factors and capturing the true prevalence of rituximab-associated HBV reactivation are essential in developing the most effective strategies for avoidance. Unfortunately, the FDA warning and the currently available data fall short of providing guidance for prophylaxis and management of at-risk patients. Furthermore, the validity of the AERS data remains in question due to potential reporting bias, incomplete data and underreporting. Regardless of impact outside of the scope of approved use, it seems the FDA and pharmaceutical industry will continue to focus their analyses and communication efforts solely on those healthcare professionals practicing within the approved indication of a medication. In the current regulatory environment, off-label use of medications in SOT will remain a mainstay of practice; therefore, it is critical that practitioners within SOT communicate with each other and American Journal of Transplantation 2014; XX: 1–9
with colleagues utilizing similar or shared medications in other specialties. Risk of HBV reactivation in the setting of standard immunosuppression for SOT patients is estimated to be approximately 5% (38). Reactivation in the setting of rituximab therapy in this population is limited to case reports, with no data available on SOT recipients who have received an allograft from an HBV positive donor (39,40). One major difference seen in the data previously discussed above was that patients received, on average, six doses of rituximab prior to HBV reactivation (22). Except for management of PTLD, rituximab is generally given as a single dose in SOT population, although subsequent doses may be required on a case-by-case basis or when required by center-specific protocols for treatment of AMR and desensitization. Due to lack of data, the appropriateness of reintroducing rituximab therapy in patients who have experienced rituximab-associated HBV reactivation remains in question. Finally, regarding additional risk factors for HBV reactivation in the setting of rituximab use, there are no available data on the potential impact of commonly administered immunosuppressive medications in the SOT population. Future study in this area is warranted, specifically in the setting of aggressive immunosuppressive protocols for desensitization prior to transplantation or the treatment of active rejection. The lack of systematic data for rituximab-associated HBV reactivation in the SOT population is disquieting. Although direct-acting antiviral HBV therapies are relatively safe, not 7
Martin et al
knowing the true risk of HBV reactivation makes initial judgments on the use of prophylactic strategies difficult. Further, the efficacy of prophylactic strategies including preferred agent, dosing and length of therapy remains unclear. Careful multicenter retrospective evaluations should be able to elucidate reactivation rates among SOT patients, as has been done in oncology patient populations. Prospective evaluations, utilizing historical controls, could then begin to describe the effectiveness of prophylactic regimens. Until that time, the use of rituximab in SOT will likely become more widespread for a variety of immunologic indications; the FDA recommendation for universal screening in all patients considered for therapy should be embraced by the SOT community. Routine screening for HBsAg, anti-HBc and anti-HBs is already engrained in the current culture of evaluating patients prior to transplantation or donation. Because HBV infection can occur posttransplantation, these same principles and systems that ensure patient safety prior to transplant must be adopted into our posttransplant care, especially when considering the use of potent immunosuppressive medications such as rituximab. We recommend that those patients with HBsAg[þ] or HBsAg[]/anti-HBc[þ] be administered antiviral prophylaxis immediately prior to the initiation of rituximab and upward of 6 months after the cessation of therapy. Vaccination to HBV prior to transplantation remains the most efficacious and costeffective strategy to preventing HBV infection in the SOT population.
8. 9.
10. 11.
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14. 15. 16.
17.
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Disclosure 19.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. 20.
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