Hepatitis B reactivation after therapy for non-Hodgkin lymphoma: A case report with review of literature

2013 ◽  
Vol 21 (3-4) ◽  
pp. 151-154 ◽  
Author(s):  
Gorana Matovina-Brko ◽  
Maja Ruzic ◽  
Milotka Fabri ◽  
Lazar Popovic ◽  
Ivana Kolarov-Bjelobrk ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Antiviral Therapy ◽  
Cancer Patients ◽  
Malignant Disease ◽  
Liver Enzymes ◽  
Antiviral Treatment ◽  
Immunosuppressive Treatment ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Anticancer Treatment

The natural course of hepatitis B virus (HBV) infection depends on the immune status of the host. In cancer patients, as the consequence of immune suppression due to chemotherapy and malignant disease itself, the balance between replicative potential of the virus and immune response of the host is disrupted leading to acute HBV infection or reactivation. We present a case of HBsAg positive, diffuse large B cell gastric lymphoma patient CD20+ staged IB, treated with six cycles of R-CHOP protocol and two cycles with rituximab monotherapy. Five months after the successful anticancer treatment, patient developed reactivation of chronic HBV infection (ten-fold increase in liver enzymes, HBsAg+, IgM antiHBc+, HBeAg(-), and HBV DNA 5?106 copies/ml). Antiviral therapy with lamivudine was started. Four weeks after the antiviral therapy initiation liver enzymes were in normal ranges. One year after the start of antiviral treatment HBV DNA PCR test did not detect any viral particles. The patient is in complete remission of malignant disease, and still receiving therapy with lamivudine. HBV screening in cancer patients is necessary in order to provide a prompt antiviral therapy and to prevent postponement or even cessation of planned anticancer treatment. HBsAg positive patients should start prophylactic antiviral treatment before the start of immunosuppressive treatment. Chemotherapy protocols consisting rituximab and corticosteroids significantly increase the risk of reactivation. If reactivation is diagnosed in course of chemotherapy, the therapy should be stopped and antiviral treatment should be applied as soon as possible. Treatment with lamivudine is continued at least 6 months after the chemotherapy end.

scholarly journals Hepatitis B Core-related Antigen: An Alternative to Hepatitis B Virus DNA to Assess Treatment Eligibility in Africa

2019 ◽  
Author(s):  
Yusuke Shimakawa ◽  
Gibril Ndow ◽  
Ramou Njie ◽  
Harr Freeya Njai ◽  
Kazuaki Takahashi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Therapy ◽  
Characteristic Curve ◽  
Scale Up ◽  
Treatment Algorithm ◽  
Hbv Dna ◽  
Hbv Infection ◽  
B Virus ◽  
Treatment Naïve

Abstract Background To eliminate hepatitis B virus (HBV) infection, it is essential to scale up testing and treatment. However, conventional tools to assess treatment eligibility, particularly nucleic acid testing (NAT) to quantify HBV DNA, are hardly available and affordable in resource-limited countries. We therefore assessed the performance of a novel immunoassay, hepatitis B core-related antigen (HBcrAg), as an inexpensive (US$ <15/assay) alternative to NAT to diagnose clinically important HBV DNA thresholds (≥2000, ≥20 000, and ≥200 000 IU/mL) and to select patients for antiviral therapy in Africa. Methods Using a well-characterized cohort of treatment-naive patients with chronic HBV infection in The Gambia, we evaluated the accuracy of serum HBcrAg to diagnose HBV DNA levels and to indicate treatment eligibility determined by the American Association for the Study of Liver Diseases, based on reference tests (HBV DNA, hepatitis B e antigen, alanine aminotransferase, liver histopathology, and/or FibroScan). Results A total of 284 treatment-naive patients were included in the analysis. The area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum HBcrAg were 0.88 (95% confidence interval [CI], .82–.93), 83.3%, and 83.9%, respectively, to diagnose HBV DNA ≥2000 IU/mL; and 0.94 (95% CI, .88–.99), 91.4%, and 93.2% for ≥200 000 IU/mL. A simplified treatment algorithm using HBcrAg without HBV DNA showed high AUROC (0.91 [95% CI, .88–.95]) with a sensitivity of 96.6% and specificity of 85.8%. Conclusions HBcrAg might be an accurate alternative to HBV DNA quantification as a simple and inexpensive tool to identify HBV-infected patients in need of antiviral therapy in low- and middle-income countries.

scholarly journals Benefits and Risks of Antiviral Treatment during Pregnancy in Patients with Chronic Hepatitis B

2021 ◽  
Vol 10 (11) ◽  
pp. 2320
Author(s):  
Yoon Seok Lee ◽  
Soo Min Bang ◽  
Young-Sun Lee
Keyword(s):  
Hepatitis B ◽  
Antiviral Therapy ◽  
Antiviral Treatment ◽  
Hbv Infection ◽  
World Health ◽  
Chronic Hbv Infection ◽  
B Virus ◽  
Chronic Hbv ◽  
Health Organization ◽  
Meta Analyses

Hepatitis B virus (HBV) is a main cause of chronic liver disease worldwide and can lead to severe liver diseases. The World Health Organization has planned to eliminate viral hepatitis, including hepatitis caused by HBV and hepatitis C virus, by 2030. As mother-to-child transmission (MTCT) of HBV is a main cause of chronic HBV infection, MTCT prevention is the main target to reduce the risk of chronic HBV infection and eliminate the disease. Recent clinical trials and meta-analyses found that antiviral therapy could prevent MTCT effectively in mothers with ≥200,000 IU/mL of HBV DNA, in combination with serial vaccination and hepatitis B immune globulin administration in infants. Despite the preventive role of antivirals for MTCT of HBV, there are several concerns regarding antiviral therapy with respect to the safety of the mother and fetus during pregnancy. This review summarizes the benefits and risks of antiviral treatment during pregnancy in women with chronic HBV infection.

scholarly journals Absence of Hepatitis B Resistance Mutants before Introduction of Oral Antiviral Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Martin Moehlen ◽  
Maria De Medina ◽  
Mary Hill ◽  
Lennox Jeffers ◽  
Eugene R. Schiff ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Antiviral Therapy ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Drug Resistant ◽  
Induced Mutations ◽  
Resistance Mutations ◽  
Chronic Hbv Infection ◽  
Treatment Naïve ◽  
Chronic Hbv

Introduction. The aim of this study was to assess whether hepatitis B virus drug resistant mutations antedated the widespread use of nucleos(t)ide analogues in treatment naïve patients. A number of reports have suggested that drug resistant mutants can be detected in apparently treatment naïve patients. Study. Fifty deidentified serum samples collected from 1986 to 1992 from patients with replicative chronic HBV infection at the University of Miami were genotyped and tested for resistance mutations using a line probe assay InnoLiPA HBV DR v2/v3. Serum HBV DNA was measured. All patients had documented chronic HBV infection with a detectable viral load, HBeAg seropositivity, and absence of HIV infection. Results. Of the 50 individuals included, 86% were male, mean age was 40 ± 12 years, and mostly genotype A. The mean HBV DNA was 126 pg/mL (range 6.4 to 557.0). No mutations were identified. Conclusions. The absence of drug induced mutations in these sera collected several years prior to the introduction of oral antiviral therapy suggests that these mutations do not occur in treatment naïve populations. Detection of drug resistance in an apparently treatment naïve subject suggests either unrecognized prior antiviral therapy or infection by an inoculum from a treatment experienced patient.

scholarly journals Comparison of Anti-Hepatitis B Virus Activities of Lamivudine and Clevudine by a Quantitative Assay

2003 ◽  
Vol 47 (1) ◽  
pp. 324-336 ◽  
Author(s):  
Ayman M. Abdelhamed ◽  
Colleen M. Kelley ◽  
Thomas G. Miller ◽  
Phillip A. Furman ◽  
Edward E. Cable ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Treatment ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Extracellular Dna ◽  
Quantitative Assay ◽  
Hbv Replication ◽  
B Virus

ABSTRACT In this study, we used a quantitative assay to measure the concentration-dependent effects of antivirals on extracellular hepatitis B virus (HBV) DNA as well as on different cytoplasmic and nuclear forms of HBV DNA that participate in HBV replication. HBV recombinant baculovirus, which efficiently delivers the HBV genome to HepG2 cells, was used for this study because (i) antivirals can be administered prior to initiation of HBV infection or after HBV infection and (ii) sufficiently high HBV replication levels are achieved that HBV covalently closed circular (CCC) DNA can be easily detected and individual HBV DNA species can be quantitatively analyzed separately from total HBV DNA. The results showed that the levels of HBV replicative intermediate and extracellular DNA decreased in a concentration-dependent fashion following antiviral treatment. The 50% effective concentration (EC50) and EC90 values and the Hill slopes differed for the different HBV DNA species analyzed. The data clearly indicated that (i) nuclear HBV DNAs are more resistant to antiviral therapy than cytoplasmic or extracellular HBV DNAs and (ii) nuclear HBV CCC DNA is more resistant than the nuclear relaxed circular form. This report presents the first in vitro comparison of the effects of two antivirals administered prior to initiation of HBV infection and the first thorough in vitro quantitative study of concentration-dependent antiviral effects on HBV CCC DNA.

scholarly journals PREVALENCE OF OCCULT HEPATITIS B INFECTION IN IRANIAN CANCER PATIENTS BEFORE CHEMOTHERAPY TREATMENT

2016 ◽  
Vol 53 (3) ◽  
pp. 175-179 ◽  
Author(s):  
Mahmud BAGHBANIAN ◽  
Mehdi HALVANI ◽  
Hassan Salman ROGHANI ◽  
Mohammad Hassan LOTFI ◽  
Mohammad Frahat YAZDI ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Cancer Patients ◽  
Hepatitis B Surface Antigen ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Hepatitis B Infection ◽  
Occult Hbv Infection ◽  
Occult Hepatitis ◽  
Occult Hbv ◽  
Occult Hepatitis B

ABSTRACT Background Occult hepatitis B infection is characterized by negative hepatitis B surface antigen (HBsAg) and also detectable hepatitis B virus (HBV) -DNA, with or without hepatitis B core antibody (anti-HBc). HBV reactivation in individuals under immunosuppressive therapy is critical, occurring in occult HBV. Objective In this study, we aimed to determine the prevalence of occult HBV infection among hepatitis B surface antigen negative in cancer patients before receiving chemotherapy. Methods Sera from 204 cancer patients who were negative for HBsAg, were tested for anti-HBc antibodies. The samples that were negative for HBsAg but positive for anti-HBc also examined for HBV-DNA by polymerase chain reaction (PCR). Results Of the 204 HBsAg negative blood samples, 11 (5.4%) samples were positive for anti-HBc antibodies. HBV-DNA was detected in 9/11 (81%) of anti-HBc positive samples. Occult HBV infection in hematological cancers was more than solid cancers, 4.8% and 4.3% respectively. There was no significant difference in HBc antibody positivity based on vaccination, previous blood transfusions, history of familial hepatitis or biochemical parameters (ALT, AST, total and direct bilirubin levels) (P>0.05). Conclusion Screening of occult HBV infection by HBsAg, HBV DNA and anti HB core antibody should be suggested as a routine investigation in cancer patients before receiving chemotherapy.

scholarly journals High Incidence of Hepatitis B Viral Reactivation in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3010-3010 ◽  
Author(s):  
Jieun Uhm ◽  
Sung-Hyun Kim ◽  
Sukjoong Oh ◽  
Dae Young Zang ◽  
Young Rok Do ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Antiviral Therapy ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Antiviral Treatment ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Antiviral Prophylaxis ◽  
Tki Treatment ◽  
Hbs Ag

Abstract Background: Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection undergoing cytotoxic or immunosuppressive therapy. Currently, BCR-ABL1 tyrosine kinase inhibitors (TKIs) have been a standard of first-line treatment for chronic myeloid leukemia (CML) about last two decades. As there have been several case reports of HBV reactivation in CML patients treated with TKIs, the test for hepatitis B infection before initiating TKIs is recommended. Therefore, this study aimed to evaluate the risk of HBV reactivation in a large cohort of CML patients on TKIs treatment. Methods: We retrospectively reviewed the medical records of 1817 patients, who were diagnosed with CML and had available HBV serology between 2001 and 2017 from St. Mary's Hospital, Seoul, Korea. Results: Among 1817 patients, 76 patients (4.2%) were HBs-antigen (HBs-Ag) positive and 1741 (95.2%) were HBs-Ag negative. 302 patients (17.3%) of 1741 HBs-Ag negative patients were HBc-antibody positive indicating past infection of HBV. After exclusion of 7 patients who did not receive TKIs treatment, 69 patients were analyzed for HBV reactivation. The median age at diagnosis of CML was 42 (range 21-73) years and 44 (64%) were males. Median duration of follow-up from the recognition of HBs-Ag was 66.7 months (range, 2.4 - 192.7 months). Of 69 patients, a patient had been on antiviral therapy for chronic HBV infection before the diagnosis of CML. Eighteen patients (26% of 68) received antiviral prophylaxis prior to or concomitantly with the initiation of TKIs. Additional 4 patients were simultaneously initiated antiviral treatment with TKIs due to the evidence of active HBV infection such as the high titer of HBV DNA or elevated level of Alanine aminotransferase. Among 46 patients who did not receive antiviral prophylaxis, 12 patients (26%; 95% CI, 12-36%) eventually required antiviral treatment due to the development of active HBV hepatitis while on TKI therapy. HBV reactivation according to each TKI treatment was developed in 7 patients with imatinib, 2 patients in dasatinib, 1 patient in nilotinib, and 1 patient in radotinib therapy. One patient developed HBV reactivation permanently discontinued TKI therapy. Median time to HBV reactivation from CML diagnosis was 22.1 (range, 6.3-124.6 months) months. Median duration of antiviral therapy of 35 patients who received antiviral therapy was 38.2 months (95% CI, 25.7 ~ 50.7 months). 9 patients were off antiviral therapy at the last follow-up, 5 patients from prophylaxis group and 4 patients from treatment group. There was no difference in the duration of antiviral treatment between prophylactic and treatment groups. The initial choice of antiviral therapy as prophylaxis or treatment were entecavir for 14 (41% of 34), lamivudine for 8 (24%), tenofovir for 8 (24%), telbivudine for 3 (9%), and adefovir for 1 (3%). Conclusion: We evaluated HBV reactivation in a large cohort of HBs-Ag positive patients with CML from a single center, who received TKIs treatment. The reactivation rate of HBV was high at 26% without antiviral prophylaxis, which strongly support the routine screening of HBV serology prior to initiation of TKI therapy to identify HBs-Ag positive patients and the close monitoring of hepatic functions and HBV serology during TKI therapy. Given the high incidence of HBV reactivation with TKI treatment, concomitant antiviral prophylaxis with TKIs should be considered in HBs-Ag positive patients receiving TKI treatment. Figure. Figure. Disclosures Kim: Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Prevalence of detectable HBV DNA in cancer patients with resolved HBV infection (HBsAg (-) HBcAb (+) and its evolution after cytotoxic chemotherapy.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 194-194
Author(s):  
Taral Ramesh Shah ◽  
Huo Xiang Zheng ◽  
Pouyan Gohari ◽  
Maxim Shulimovich ◽  
Yiwu Huang ◽  
...  
Keyword(s):  
Antiviral Therapy ◽  
Cancer Patients ◽  
Seroconversion Rate ◽  
Protective Role ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Hbv Reactivation ◽  
Asian Patients ◽  
Solid Malignancies ◽  
Prophylactic Antiviral Therapy

194 Background: Reactivation of hepatitis B virus (HBV) has been widely reported in HBsAg+ cancer patients undergoing chemotherapy, mainly in patients with lymphoma and breast cancer who received Rituximab and Adriamycin based chemotherapy. Reactivation of HBV has also been reported in a few patients who had previous exposure and resolved HBV infection (HBsAg-, HBcAb+). However there is no consensus as to whether prophylactic antiviral therapy should be used for this group, or whether the presence HBsAb plays a further protective role. Methods: We retrospectively and prospectively identified cancer patients undergoing chemotherapy who have HBsAg-, HBcAb+ status. Their HBV DNA levels and serial liver functions were followed. We aimed to evaluate the prevalence of detectable HBV DNA and HBV seroconversion rate after chemotherapy. Results: Between 11/2011 to 6/2013, 124 patients were screened and 51 (41%) had pretreatment HBsAg-, HBcAb+ status. Forty two (82%) patients were of Asian descent; 18 (35%) were males and 33 (65%) were females. Median age was 60 years with a range of 28 to 84 years. Forty seven patients (92%) received chemotherapy for solid malignancies while 4 (8%) received rituximab. Only one patient (2%) had detectable HBV DNA prior to treatment and received baraclude for prophylaxis. Fifteen patients (29%) had HBsAg-, HBcAb+, HBsAb- status, 36 (71%) had HBsAg-, HBcAb+, HBsAb+ status. Serial LFTs were followed over a median chemotherapy duration of 4 months (1 to 18 months). 2 had transient increase; 13 showed persistent but stable elevation related to tumor in the liver; 4 patients were tested for HBV DNA at LFT elevation and were negative. No patient had persistent or worsening LFT related to HBV reactivation. Conclusions: The prevalence of HBsAg-,HBcAb+ cancer patients is very high in South Brooklyn, NY, predominantly in Asian patients. Prevalence of detectable baseline HBV DNA is extremely low, even in isolated HbcAb positive patients and there was no seroconversion of HBV during chemotherapy, irrespective of HBsAb status. Prophylactic antiviral therapy is unnecessary.

scholarly journals A noninvasive model to predict liver histology for antiviral therapy decision in chronic hepatitis B with alanine aminotransferase < 2 upper limit of normal

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shanshan Chen ◽  
Haijun Huang ◽  
Wei Huang
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Liver Biopsy ◽  
Antiviral Therapy ◽  
Alanine Aminotransferase ◽  
Antiviral Treatment ◽  
Training Group ◽  
Liver Histology ◽  
Validation Group ◽  
Upper Limit

Abstract Background At present, most assessments of liver fibrosis staging mainly focus on non-invasive diagnostic methods. This study aims to construct a noninvasive model to predict liver histology for antiviral therapy in chronic hepatitis B (CHB) with alanine aminotransferase (ALT) < 2 times upper limit of normal (ULN). Methods We retrospectively analyzed 577 patients with CHB who received liver biopsy and whose ALT was less than 2 ULN. Then they were randomly divided into a training group and a validation group. Through logistic regression analysis, a novel predictive model was constructed in the training group to predict significant changes in liver histology [necro-inflammatory activity grade (G) ≥ 2 or fibrosis stage (S) ≥ 2] and then validated in the validation group. Results If liver biopsy showed moderate or severe inflammation or significant fibrosis, antiviral treatment was recommended. Aspartate aminotransferase (AST), anti-hepatitis B virus core antibody (anti-HBC) and glutamine transpeptidase (GGT) were identified as independent predictors for antiviral therapy, with area under the ROC curve (AUROC) of 0.649, 0.647 and 0.616, respectively. Our novel model index, which combined AST, anti- HBC and GGT with AUROC of 0.700 and 0.742 in training set and validation set. Conclusions This study established a noninvasive model to predict liver histology for antiviral treatment decision in patients with CHB with ALT < 2 ULN, which can reduce the clinical needs of liver biopsy.

Real-World Experience of Telbivudine and Lamivudine as Antiviral Prophylaxis for Chemotherapy-Related Hepatitis B Reactivation

2021 ◽  
Vol 15 (1) ◽  
pp. 11
Author(s):  
Lianda Siregar ◽  
Imelda Maria Loho ◽  
Agus Sudiro Waspodo ◽  
Siti Nadliroh ◽  
Rahmanandhika Swadari ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Medical Records ◽  
Antiviral Treatment ◽  
Hbv Dna ◽  
Hbv Reactivation ◽  
Lamivudine Therapy ◽  
Number Of Patients ◽  
Group 2 ◽  
Good Treatment Option ◽  
Hbs Ag

Background: There is currently no data regarding the efficacy of prophylactic telbivudine in hepatitis B patients undergoing chemotherapy. This study aims to describe the results of preemptive telbivudine and lamivudine to prevent chemotherapy-related HBV reactivation.Methods: The medical records of all patients with HBsAg positive or HBs-Ag negative, anti-HBc positive, who were referred to the hepatology clinic between May 2014 and December 2016, were retrospectively reviewed. As this is a descriptive study, no statistical analysis was done.Results: A total of 52 patients with prophylactic telbivudine or lamivudine therapy were included, with 26 patients in each group. Rituximab-based treatment was given in nine and five patients in the telbivudine and lamivudine group, respectively. The number of patients who completed antiviral treatment up to six months after chemotherapy was 17 patients in each group. There was less incidence of HBV reactivation in the telbivudine group (2 of 17 patients, 11.8%) than in the lamivudine group (7 of 17 patients, 41.2%). Delayed reactivation was noticed in 1 of 2 patients in the telbivudine group and 3 of 7 patients in the lamivudine group. The median log10[HBV DNA] at reactivation was 4.52 (1.70 – 8.35) IU/mL. Severe hepatitis was observed in two patients in the lamivudine group and one patient in the telbivudine group. Of 34 patients who completed antiviral treatment, two patients died due to primary cancer. No interruption of chemotherapy or mortality due to hepatitis was noticed in both groups.Conclusions: Preemptive telbivudine or lamivudine in HBsAg positive or HBsAg negative, anti-HBc positive patients seems to be a good treatment option.

scholarly journals Molecular Diagnosis in Differentiating Active and Inactive Forms of Hepatitis B Virus Carriers

2018 ◽  
Vol 26 (10) ◽  
pp. 41-45
Author(s):  
Salah Tofik Jalal Balaky ◽  
Saeed Ghulam Hussain ◽  
Amer Ali Khaleel ◽  
Furat Tahseen Sabeer ◽  
Ahang Hasan Mawlood
Keyword(s):  
Nucleic Acid ◽  
Hepatitis B ◽  
Cross Sectional Study ◽  
Hbv Dna ◽  
Hbv Infection ◽  
Detection Methods ◽  
Rt Pcr ◽  
Cross Sectional ◽  
Blood Samples ◽  
Acid Test

Background & objectives: Introducing a nucleic acid test program is aimed to diagnose and reduces the risk of viral infection or transmission. DNA assay for HBV can detect infection in the windows period, chronic occult infection and can discriminate between active and inactive HBV infection. This cross-sectional study designed to diagnose, analyze HBV infection and to differentiate active from inactive infection based on viral DNA detection. Methods: Blood samples were collected from 256 patients previously diagnosed on the clinical ground as hepatitis B seropositive in Erbil Central Lab. The viral nucleic acid quantitative assessment was done for the collected samples using RT-PCR. Q-square was performed for statistical analysis. Results: Out of 256 collected blood samples 93 (36.3%) showed HBV-DNA positive titers above 50 IU/ml. Among positive subjects, 67 (72.04%) was categorized as inactive carriers (˂ 2000-20.000 IU/ml HBV-DNA titers). Conclusions: The data produced from this study confirmed the importance of the RT-PCR technique in sensitivity and reliability as a superior diagnostics tool specifically in differentiating active from inactive HBV carriers.

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