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      Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: The Preblin study

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          Abstract

          Background

          Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy.

          Methods

          PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc-positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety.

          Results

          Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events.

          Conclusion

          In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis.

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          Most cited references 34

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          Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors.

          Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. As chemotherapy is used increasingly in cancer patients, HBV reactivation during cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during chemotherapy. However, corresponding data for patients with other malignancies undergoing cytotoxic chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received cytotoxic chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during chemotherapy. It is concluded that in patients with chronic HBV infection under chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.
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            Reactivation of hepatitis B.

             J Hoofnagle (2009)
            Reactivation of hepatitis B refers to the abrupt increase in hepatitis B virus (HBV) replication in a patient with inactive or resolved hepatitis B. Reactivation can occur spontaneously, but more typically is triggered by immunosuppressive therapy of cancer, autoimmune disease, or organ transplantation. Reactivation can be transient and clinically silent, but often causes a flare of disease that can be severe resulting in acute hepatic failure. Most instances of reactivation resolve spontaneously, but if immune suppression is continued, re-establishment of chronic hepatitis occurs which can lead to progressive liver injury and cirrhosis. The best-described instances of reactivation occur in hepatitis B surface antigen (HBsAg) carriers with inactive or minimally active disease who are given cancer chemotherapy for lymphoma or leukemia. Typically, serum HBV DNA rises during chemotherapy, followed by a disease flare and HBV DNA clearance with immune reconstitution after chemotherapy is stopped. Special forms of reactivation occur after solid organ and bone marrow transplantation in which chronic infection often results. Several randomized, placebo-controlled trials have shown that reactivation can be prevented by antiviral prophylaxis. Routine prophylaxis is therefore recommended for persons with HBsAg undergoing cancer chemotherapy or transplantation, but major questions remain. Which patients should be screened for HBsAg and should all be treated? Which antiviral should be used and for how long? Should persons with resolved hepatitis B without HBsAg receive prophylaxis? Future research should address the underlying molecular mechanisms of reactivation as well as its optimal means of diagnosis, treatment, and prevention in different patient populations.
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              American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.

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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Supervision
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 September 2017
                2017
                : 12
                : 9
                Affiliations
                [1 ] Liver Unit, Hospital Vall Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain
                [2 ] Department of Hepatology, Hospital Doce de Octubre, Madrid, Spain
                [3 ] Department of Hepatology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
                [4 ] Department of Hepatology, Hospital del Mar, Barcelona, Spain
                [5 ] Department of Hepatology, Hospital de Donostia, San Sebastián, Spain
                [6 ] Department of Hepatology, Hospital Universitario i Politécnico La Fe, Valencia, Spain
                [7 ] Department of Hepatology, Fundación Hospital de Alcorcón, Madrid, Spain
                [8 ] Department of Hepatology, Hospital Nuestra Señora de Valme, Seville, Spain
                [9 ] Department of Gastroenterology, Hospital de Getafe, Madrid, Spain
                [10 ] Department of Hematology, Hospital Ramón y Cajal, Madrid, Spain
                [11 ] Department of Hepatology, Hospital La Paz, Madrid, Spain
                [12 ] Department of Hepatology, Hospital Central de Asturias, Oviedo, Spain
                [13 ] Department of Gastroenterology, Hospital de Navarra, Pamplona, Spain
                [14 ] Department of Hepatology, Hospital Clínico Lozano Blesa, Zaragoza, Spain
                [15 ] Department of Infectious Diseases, Hospital do Meixoeiro, Vigo, Spain
                [16 ] Department of Gastroenterology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain
                [17 ] Pharmacoeconomics & Outcomes Research Iberia, Madrid, Spain
                The Chinese University of Hong Kong, HONG KONG
                Author notes

                Competing Interests: The authors have declared that no competing interests exist. María Yébenes (to Pharmacoeconomics & Outcomes Research Iberia) response: I confirm that my commercial affiliation does not alter my adherence to all PLOS ONE policies on sharing data and materials.

                Article
                PONE-D-17-05523
                10.1371/journal.pone.0184550
                5595327
                28898281
                © 2017 Buti et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 3, Pages: 14
                Product
                Funding
                Medical Department of Gilead Sciences supplied the medications used in this study and its funding regardless of the study results. Medical Department of Gilead Sciences had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis B virus
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