Acute Hepatitis B in a Patient with Antibodies to Hepatitis B Surface Antigen Who Was Receiving Rituximab

Abstract

The review article in this issue by Goldberg et al. and the accompanying editorial by Hale and Zinberg were sent to G.D. Searle, the manufacturer of misoprostol, which offers the following:To the Editor: The article by Goldberg et al. on misoprostol and pregnancy 1 , the accompanying editorial by Hale and Zinberg, 2 and the events surrounding the approval by the Food and Drug Administration (FDA) of mifepristone for the termination of pregnancy raise important issues. Searle has been invited to clarify its position and actions in this regard. We at Searle share the overriding concern of Hale and Zinberg that physicians be supported in providing the most appropriate care for their patients. We also wish to emphasize our commitment to working collegially with all relevant parties.Our product, Cytotec (misoprostol), was approved by the FDA in 1988 for the prevention of gastric ulcers associated with the use of nonsteroidal antiinflammatory drugs. This is the only approved indication for Cytotec, and we are prohibited by FDA regulations from promoting or even suggesting its use for any other purpose. Since 1988, the Cytotec label has always carried a "black box" warning against its use in pregnant women because of its potential to cause serious adverse events, including miscarriage.Our letter of August 23, 2000, to health care professionals was, therefore, an elaboration of this long-standing warning, consistent with our continuing duty to inform health care professionals about possible risks. It resulted from lengthy discussions between Searle and the FDA after reports were received of uterine rupture in connection with the offlabel use of Cytotec in pregnant women. The FDA requested that we make a labeling change to clarify further the serious risks and to consider sending a letter to health care professionals. Our August 23 letter was a result of this dialogue and was developed in consultation with the FDA. We continue to work with the FDA to resolve issues related to the language in the label regarding the risk of adverse events. However, these discussions have not included consideration of any alteration to Cytotec's approved indication.We particularly wish to clarify the timing of the letter dated August 23. The fact that it was distributed just over a month before the FDA approval of mifepristone was entirely coincidental. We had no specific knowledge about the status of regulatory action on mifepristone, which had been pending for several years.With regard to the article by Goldberg et al., the authors find evidence of efficacy when misoprostol is used in pregnant women. However, as the authors correctly note, "misoprostol is not approved for any of these indications in the United States." We fully support the role of physicians, using their professional judgment, to prescribe an approved pharmaceutical product for a use outside of its FDA-approved indication in the best interest of their patients, on the basis of published research, expert clinical opinion, or their own clinical experience.In conclusion, as ...

Hepatitis B reactivation after chemotherapy: two decades of clinical research

“…With the increasing prevalence of HIV infection, HBV reactivation has also been observed in HBV-infected subjects with advanced immune deficiency due to HIV infection [22][23][24][25][26][27]. Hepatitis due to HBV reactivation has not only been reported in HBsAg-positive patients, HBeAg-positive [6,[28][29][30] or HBeAg-negative [31][32][33][34][35][36][37][38][39][40][41] subjects who were treated with chemotherapy and transplantation but also in HBsAg-negative patients who had past HBV infection (hepatitis B surface antibody; antiHBs positive and hepatitis B core antibody; anti-HBc positive) [42][43][44][45][46][47][48][49], especially those treated with rituximab or alemtuzumab-containing chemotherapy [50][51][52][53][54][55].…”

“…In the transplant setting, such as bone marrow transplant [1-3, 19, 20, 61], heart transplant [62], and kidney transplant [63,64], the use of immunosuppressive therapy is mandatory to prevent graft rejection and HBV reactivation has been well characterized. Recently, the advance in therapies based on mechanisms that target critical molecular pathways of tumors has evoked considerable interest and among them, rituximab (anti-CD20) [50][51][52][53][54], alemtuzumab (anti-CD52) [55], infliximab (anti-TNF) [65], have been associated with HBV reactivation in HBsAg-positive as well as HBsAgnegative patients. These agents cause profound and longlasting immunosuppression, which may account for the risk of HBV reactivation following treatment.…”

HBV reactivation with fatal fulminating hepatitis during rituximab treatment in a subject negative for HBsAg and positive for HBsAb and HBcAb

“…8 The majority of cases have been reported in HBsAgpositive patients, but also, in few instances, in HBsAgnegative and anti-hetpatitis B surface antigen (anti-HBs)-positive subjects. 9,10 Here, we report a fatal case of HBV fulminating hepatitis that occurred despite the administration of antiviral therapy with lamivudine, in a man treated with rituximab for B-chronic lymphocytic leukemia, who was HBsAgnegative and positive for anti-hepatitis B core antigen (antiHBc) and anti-HBs, suggestive of previous exposure to HBV, with recovery.…”

Screening for and management of hepatitis B virus reactivation in patients treated with anti-B-cell therapy

“…HBV reactivation has been found, not only in patients seropositive for hepatitis B surface antigen (HBsAg), [1][2][3] but also in those with resolved HBV infection who are seronegative for HBsAg but seropositive for antibodies against hepatitis B core antigen (anti-HBc) and/or antibodies against HBsAg (anti-HBs). 1,[4][5][6][7][8][9] Rituximab ϩ steroid-containing chemotherapy has been identified recently as an important risk factor for HBV reactivation in patients with resolved HBV infection. 5,6 Rituximab is a chimeric mousehuman monoclonal antibody that targets the CD20 molecule.…”