Hepatitis B Virus Reactivation Research Articles

Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, ~257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B virus reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV coinfected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review, factors associated with HBVr, particularly medication-related risks, are explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Occult hepatitis B and HIV infection.

Occult hepatitis B virus (HBV) infection, so-called occult B infection (OBI), is defined by the recognition of HBV-DNA in the absence of serum hepatitis B surface antigen (HBsAg). The HBV-DNA genome in OBI is fully replication competent and produced in the liver, characteristically with low-level HBV-DNA fluctuations in the bloodstream. The OBI status remains between chronic (HBsAg +) and resolved (anti-HBs +) phases in the natural history of HBV infection. The clinical interest in OBI has increased because of its potential for overt HBV reactivation under immunosuppression as well as for HBV transmission, well established in recipients of blood transfusions and/or organ transplants. Given the shared transmission routes for HIV and HBV, earlier reports claimed that OBI was more frequent in AIDS patients. By contrast, the current scenario shows that OBI is negligible in the HIV population. One explanation is that HBV immunization and recall vaccination campaigns have been very active in this group. A second and most important reason points to the wide use of antiretroviral regimens that include anti-HBV active agents, that is, tenofovir, lamivudine, and/or emtricitabine. They are recommended either as treatment for all HIV carriers or as pre-exposure prophylaxis for uninfected individuals at risk. The consequences are that HBV reactivations associated with HIV-related immunodeficiency have become very rare. Furthermore, HBV suppression with these antivirals has markedly reduced the likelihood of transmission from OBI carriers and/or acquisition by uninfected exposed individuals. Enthusiasm unabated, however, new tenofovir-sparing antiretroviral regimens are becoming popular and might account for a resurgence of OBI in the HIV setting.

PIN149 RETROSPECTIVE SURVEY FOR HEPATITIS B VIRUS REACTIVATION DURING IMMUNOSUPPRESSIVE THERAPIES FOR RHEUMATOID WITH ADMINISTRATIVE DATA

Risk of hepatitis B virus (HBV) reactivation has increased because of advances in immunosuppressive therapies. People having a previously-resolved HBV infection and those with serum HBs-antigen positivity are likely to develop liver injuries after the therapies. However, the risk of HBV reactivation for rheumatoid arthritis (RA) patients is still unclear. This study described a validity of detecting prHBV infection from administrative data by comparing with chart abstraction, and to determine an incidence of HBV reactivation during immunosuppressive therapy of Japanese RA patients. Adult patients who had been diagnosed with RA between 1 April 2011 and 31 March 2015 were extracted from the Medical Information Analysis (MIA) databank managed by the Clinical Research Center at the National Organization Hospitals (NHO) Headquarters. We also conducted chart abstraction in three hospitals to verify whether those patients actuary had records of prHBV infection, de novo hepatitis, and HBsAg carriers. A positive predictive value (PPV) of the algorithm of HBV-DNA testing with immunosuppressive therapy performed four times or more / year for the detection of prHBV infection from administrative data and an incidence rate of HBV reactivation among preHBV infections during immunosuppressive therapy for RA were calculated. The PPV and its 95% confidence interval (CI) of administrative data for the identification of suspected prHBV infections was 85.8% (95% CI: 81.7% - 89.3%). The incidence rate of de novo hepatitis was 1.23 / 100 person-years. The main concerns of epidemiological studies using administrative health data are lack of health information to identify true patients and the validity of recorded diagnoses and other information is critical. For HBV reactivation, monitoring data of serum HBV-DNA levels after immunosuppressive therapies were unavailable in the database and the chart review was useful approach. This validity study provided a good example to help our future HBV projects.

ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage.

Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.

Cost-Effectiveness Analysis of Screening for Hepatitis B Virus Infection in Patients With Solid Tumors Before Initiating Chemotherapy

Patients with solid tumors who undergo chemotherapy have an increased risk of hepatitis B virus (HBV) reactivation, but a low proportion of these patients are screened for HBV infection and guidelines make conflicting recommendations. Further, the cost-effectiveness of newer treatments for HBV prophylaxis has not been examined for this population. We aimed to analyze the cost-effectiveness of HBV screening before chemotherapy for patients with solid tumors. We compared 3 HBV screening strategies (screen all, screen only high-risk patients, or screen none) using a Markov model of a population of adults in the United States who initiated chemotherapy for a solid tumor. We modeled use of entecavir prophylaxis for HB surface antigen (HBsAg)-positive patients and surveillance for HBsAg-negative patients who are positive for HBV core antibody. The Markov cycle length was 1 year, with model simulation for up to 5 years. The screen all strategy was the most cost effective, with an incremental cost-effectiveness ratio of $42,761 compared to screening only high-risk patients. The screen none strategy was less effective and less costly than screening all patients or only high-risk patients. The screen-all strategy was the most cost effective for all estimates of prevalence of HBsAg-positive patients and estimates of HBV reactivation in HBsAg-positive patients. Screening only high-risk patients was the most cost-effective strategy when more than 25% of high-risk patients were screened for HBV infection. In a Markov model analysis, we found screening all patients with solid tumors for HBV infection before chemotherapy to be the most cost-effective strategy. Guidelines should consider recommending HBV tests for patients initiating chemotherapy.

288. Hepatitis B Virus Reactivation in Patients with Hematologic Malignancies after Anticancer Therapy Which Included Ibrutinib

BackgroundSeveral cases of severe bacterial, fungal, and viral infections have been reported following ibrutinib therapy. Here, we report a case of a patient with non-Hodgkin lymphoma who developed hepatitis B virus (HBV)–associated liver failure after anti-cancer treatment most recently with ibrutinib. We also review reported cases of HBV reactivation (HBVr) after ibrutinib.MethodsWe searched the Medline and Embase databases and identified 5 patients with HBVr related to ibrutinib for a total of 6 study patients, including our case (figure). HBV-related outcomes were defined according to the 2018 AASLD HBV guidance document.ResultsAll 6 patients were men and most (5 or 83%) had chronic lymphocytic leukemia and past HBV infection (table). Three patients (50%) developed HBV-related hepatitis and 2 of them progressed to liver failure. Four patients (67%) had a remote history (≥24 months) of other potential risk factors besides ibrutinib that could contribute to HBVr, including the use of direct-acting antivirals for hepatitis C co-infection (1 pt), hematopoietic cell transplant (HCT) (1 pt) and rituximab use (4 patients). HBVr occurred at least 6 months after initiation of ibrutinib in most patients (4 or 67%), with a median of 9.7 months (range, 1.5–42). In all 4 patients pretreated with rituximab, that treatment was completed at least 24 months before HBVr. Two of these patients received anti-HBV prophylaxis that was stopped 12 months after the completion of rituximab; the other 2 patients were only monitored without antivirals. The HCT recipient received anti-HBV prophylaxis per guidelines. None of the 6 patients treated with ibrutinib were receiving anti-HBV prophylaxis at the time of HBVr, but 5 patients were started on anti-HBV drugs at the first sign of HBVr. Four received entecavir and 1, tenofovir. All treated patients recovered from HBVr. No pt died of HBVr.ConclusionLife-threatening HBVr can occur following ibrutinib therapy in patients with past or chronic HBV infection. The temporal association between ibrutinib therapy and reactivation indicates that ibrutinib is the likely cause of the HBVr, and clinicians should be aware of the risk of HBVr in these patients. A provisional approach could be HBV monitoring at regular intervals with initiation of antiviral therapy at the earliest sign of HBV reactivation. Disclosures All authors: No reported disclosures.

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high‐risk groups

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)-positive for >6months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985-2002) who had anti-hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan-Meier curves. A total of 147 incident HBV infections occurred during follow-up. On initial HBsAg testing after infection (6-12months), 42 (29%) were HBsAg-positive and 105 (71%) were HBsAg-negative ('standard HBsAg seroclearance'). Of the 42 initially HBsAg-positive individuals, 22 subsequently tested HBsAg-negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg-negative and HBV DNA-negative ('delayed HBsAg seroclearance'), while 27 remained HBsAg and/or HBV DNA-positive ('chronic HBV'). The 5-year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg-positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)-co-infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at-risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct-acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co-infected MSM/PWUD are warranted prior to treatment initiation.

2401 A Case of Hepatitis B Reactivation

INTRODUCTION: It is estimated that more than two billion people around the world have been infected by hepatitis B virus (HBV). Several immunosuppressive agents have been associated with HBV reactivation (HBVr). We present a case of HBVr in a patient with ulcerative colitis (UC) treated with tofacitinib. CASE DESCRIPTION/METHODS: A 57-year-old female with UC on tofacitinib presented to the emergency department with flu-like symptoms for 2 months after being switched from azathioprine to tofacitinib. She was HBV surface antigen (HBsAg) negative, anti-HBV core antibody (anti-HBcAb) and anti-HBV surface antibody (anti-HBsAb) positive and had normal liver enzymes before initiation of tofacitinib. On initial evaluation she was febrile, hypotensive, and had lower extremity edema. Laboratory data was significant for total bilirubin 2.5 mg/dL, AST 1601 U/L, ALT 1013 U/L, positive HBsAg, anti-HBsAb, total anti-HBcAb and HBeAg, HBV DNA 10,354,246 IU/m; she had negative HBeAb, IgM antibody to HBcAg, hepatitis A, C and E antibodies. She was diagnosed with HBVr and was started on tenofovir disoproxil fumarate. Over the next two days her enzymes continued to rise and peaked at day 5. At day 7 liver enzymes started to trend down. She was later discharged on tenofovir. At the 2 month follow up liver enzymes had normalized and HBV DNA was down to 30 IU/m. DISCUSSION: Tofacitinib is a kinase inhibitor extensively studied in patients with rheumatoid arthritis and has been shown to be generally safe in multiple clinical trials. In patients with UC the data is limited. Most clinical trials excluded patients with chronic HBV infection, therefore the risk of HBVr among tofacitinib-treated patients remains unknown. HBVr is defined as an increase in HBV DNA of more than 100-fold in patients with previously detected HBV DNA, detection of HBV DNA in patients that previously had undetectable titers or when reverse seroconversion or development of detectable HBsAg occurs. In this case, the reactivation of HBV was most likely induced by tofacitinib and its suppression of various kinase signaling pathways essential for controlling immune activation and proliferation the cells responsible of preventing HBV replication. In conclusion, in patients with resolved HBV infection who are HBsAg negative and anti-HBcAb positive, periodic HBV DNA monitoring should be considered as HBVr is possible and the exact risk of reactivation remains unknown.

1837P - Impact of routine screening and preemptive treatment on hepatitis B virus reactivation (HBVr) in patients receiving chemotherapy

BackgroundGuidelines diverge about the need for systematic HBV screening for all patients starting chemotherapy. At the Centre hospitalier de l’Université de Montréal (CHUM), systematic HBV screening is requested on pre-printed chemotherapy order (PPCO) at high risk of HBVr with follow-up by a pharmacist. For all other PPCO, doctors can request HBV screening and follow-up. A decision algorithm is available for all clinicians. The aim of this study is to assess whether patients undergoing routine HBV screening could reduce the incidence of HBVr. MethodsThis is a retrospective observational study including patients who received an IV chemotherapy for cancer between July 2017 and June 2018 at the CHUM. We compared the incidence and complications of HBVr in patients with HBV screening as requested on PPCO (group 1) or on demand from the medical team (group 2) to patients who were not screened (group 3). ResultsOn a total of 1374 patients, 179 of 206 (13%) patients were screened as requested on PPCO (group 1) and 421 (30%) by the medical team (group 2). Patient characteristics, duration of treatment and follow-up for all groups are listed in the table. No difference was seen on the incidence of HBVr between screened and unscreened patients (0% vs 0.1%; p=0.36) probably because of a lack of follow-up after chemotherapy. Optimal follow-up for HBVr based on the decisional algorithm appears to be better in group 1 than group 2 (50% vs 25%; p=0.13). For patients on anti-CD20 therapy in group 1, HBV screening was done for 92% of patients which is a higher rate compare to previously reported data. In group 3, 89 patients had ALT elevation (>100U/L and x3 baseline value) during chemotherapy but only 17 patients (19%) were tested for the possibility of HBVr.Table1837PTableGroup 1 n=206 (%)Group 2 n=421 (%)Group 3 n=747 (%)Screening before chemotherapy179 (86.9)421 (100)0 (0)Nb of pts who had finished chemotherapy treatment at the time of analysis174 (84.5)402 (95.5)699 (93.6)Median duration (months) of chemotherapy (IQR)10.5 (6.4-14.4)4 (1.4-9.1)3.6 (1.6-5.6)HBsAg + Anti-HBc + HBV-DNA +0 (0) 17 (8.3) 1 (0.5)2 (0.5) 36 (8.6) 2 (0.5)-Incomplete screening5 (2.8)31 (7.4)-Antiviral prophylaxis required Antiviral prophylaxis initiated8 (3.9) 7 (3.4)3 (0.7) 3 (0.7)-Follow-up required Follow-up Optimal follow-up18 (8.7) 10 (4.9) 9 (4.4)36 (8.6) 13 (3.1) 9 (2.1)-Number of patients who had a follow-up after chemotherapy3 (1.5)5 (1.2)HBV reactivation0 (0)0 (0)1 (0.1) ConclusionsSystematic HBV detection requested on PPCO is an effective way to increase HBV screening and prevent HBVr in patients receiving chemotherapy. However, this method does not guarantee optimal follow-up and requires improvements. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureD. Martel: Honoraria (self): Abbvie Canada; Honoraria (self): Gilead Sciences Canada; Honoraria (self): Merck Canada. V. Martel-Laferrière: Research grant / Funding (self), Clinical Research Scholars - Junior 1: Fonds de la recherche en santé du Québec. S. Doucet: Honoraria (self), Advisory / Consultancy: AbbVie Canada; Honoraria (self), Advisory / Consultancy: Gilead Sciences Canada; Honoraria (self): Merck Canada; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self): Seattle Genetics. J. Adam: Honoraria (self): Amgen Canada; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AbbVie; Advisory / Consultancy: Lundbeck. All other authors have declared no conflicts of interest.

1024 A Retrospective Analysis of Hepatitis-B Reactivation in Hepatitis-C Patients Treated With Direct-Acting Antivirals Therapy

INTRODUCTION: Hepatitis B virus/hepatitis C virus (HBV/HCV) co-infection has a prevalence of 5%-10% in patients with chronic HCV patients. Direct-acting antiviral agent (DAA) have replaced Interferon (IFN)-based treatment for HCV infection given the increased HCV sustained virological response (SVR). However, the Food and Drug Administration (FDA) has issued warnings about HBV reactivation (HBV-R) in chronic HCV patients treated with DAA. We aimed to assess the HBV reactivation rate in our chronic HCV patient population treated with DAA (Ledipasvir / Sofosbuvir). METHODS: We conducted a retrospective study involving HCV patients treated with DAA at our outpatient hepatology clinic located in Erie county medical center. The goal as discussed above was to find the HBV reactivation which was defined as reverse seroconversion of HBsAg-negative patients at baseline becoming HBsAg-positive post DAA therapy with a DNA level >0 IU/mL. Patient characteristics and laboratory results at baseline and at the end of follow-up were retrospectively analyzed from electronic medical records. A chart review was completed for a total of 260 patients fulfilling the inclusion criteria. The mean age of the study population was 56.5 years. Inclusion criteria: 1-DAA therapy for HCV with confirmed SVR. 2-HBsAg-negative/HbcAb+. 3-HBV/HCV coinfection. Exclusion criteria: 1- Coinfection of HAV/HDV/HEV. 2- Decompensated cirrhosis with CPT class B/C. 3- Active HBV coinfection. 4- Undergoing immunosuppressive therapy or chemotherapy. RESULTS: Post-treatment serum samples of 260 patients were analyzed. Of these, 19.60% (51/260) of the total population was positive for HbcAb. Out of these 51 patients, 13 post-DAA treatment patients were checked for hepatitis-B DNA level to rule out the concern for reactivation. None of the patients showed any elevation in Hepatitis-B virus DNA level, i.e. undetectable. Also, no seroconversion to HbsAg+ was noticed in our population post-DAA therapy. Further detailed results will be presented in the poster during meeting. CONCLUSION: To conclude, we found no hepatitis-B virus reactivation or seroconversion to HBsAg positive state in our cohort. Our study supports the latest literature that although it has been observed in the past, HBV reactivation in exposed patients with HbcAb without positive HbsAg is very rare.

Risk of hepatitis B virus reactivation in patients with solid tumors receiving systemic chemotherapy

Abstract Background Hepatitis B virus (HBV) reactivation is known as a risk of chemotherapy in patients with hematopoietic tumors at a rate of 14 to 72%. Screening tests for HBV (HBsAg, HBsAb, HBcAb) are recommended for chemotherapy in patients with solid tumors, however there are a few reports of risk of HBV reactivation and management other than hematopoietic tumors. Patients and Methods We analyzed 18 HBV-DNA positive patients who received systemic chemotherapy for malignancies between October 2017 and February 2019. Results The 18 patients included 2 with hematopoietic tumors and 16 with solid tumors. Among them, 4 showed negative for HBsAg before chemotherapy (1 each with breast cancer, neuroendocrine carcinoma, smooth muscle sarcoma, and colon cancer), and other 12 were HBsAg-positive. One of the HBsAg-negative patients developed active hepatitis and was treated with nucleoside. The other 3 presented positive for HBV-DNA in the absence of active hepatitis through the clinical course. 11 of the 12 HBsAg-positive patients showed HBV-DNA positive, and received nucleoside analog without active hepatitis. Most of the attending physicians had not perceived HBV-positivity in the patients before notification by the hepatologists. Conclusion The treatment of hematopoietic malignancies as well as solid tumors may develop HBV reactivation. HBV screening is recommended according to guidelines before chemotherapy. The intervention of hepatologists in a hospital is necessary for all patients receiving chemotherapy.

1041 Implementation of a Chronic Hepatitis Panel to Improve Viral Hepatitis Screening in Chronic Liver Disease

INTRODUCTION: In 2015, 40,326 or 12.5 per 100,000 population died from chronic liver disease. Viral hepatitis is associated with 18.5% of chronic liver disease related deaths. The vast majority of patients with liver disease present in the chronic phase, however, Community Regional Medical Center was using an acute hepatitis panel (HAV Ab IgM, HBsAg, HBcAb IgM, and HCV Ab) to evaluate for viral hepatitis. We created and implemented a chronic hepatitis panel (HAV Ab Total, HBsAg, HBsAb, HBcAb Total, and HCV Ab) with the aim of improving screening for chronic viral hepatitis, identifying patients at risk for HBV reactivation and patients in need for HAV and HBV vaccinations. METHODS: Baseline clinical and laboratory data including the number of acute hepatitis panels were collected from July 2017 to June 2018. Post-implementation data were collected from November 2018 to April 2019. The primary outcome was the utilization of the appropriate hepatitis panel to the presenting clinical syndrome. Secondary outcomes were vaccination rates for HAV and HBV in the setting of chronic liver disease and healthcare cost utilization of patients with chronic liver disease. RESULTS: Of 17,357 patients screened, acute hepatitis panel was ordered in 40.2%, mainly in the emergency department (42%) and inpatient (40%) setting. Of these, 26.9% of acute hepatitis panels were ordered with ALT < 150 or prior to ALT results. 64.7% of patients completed chronic hepatitis panel components afterward. Chronic hepatitis panel components were ordered more than once in 47.4%. Post-implementation data was collected in 6298 patients of which, 14% completed the chronic hepatitis panel. There was a 220% increase in the number of chronic hepatitis panels ordered, from November 2018 to April 2019. The average number of hepatitis labs (panel or components) ordered per patient decreased from 3.4 to 2.2 post implementation of the chronic panel. The cost for the chronic hepatitis panel is $214.20 compared to $325.38 for the acute hepatitis panel, reflecting a cost savings of 34% per panel. This is in addition to the projected savings from the decrease in the inappropriate ordering of labs. CONCLUSION: The chronic hepatitis panel can improve screening for chronic viral hepatitis, and potentially improve vaccination rates against Hepatitis A and Hepatitis B, as well as help prevent HBV reactivations, while lowering costs, in chronic liver disease. Longitudinal studies are needed to assess the impact of chronic hepatitis panel on disease outcomes.

2400 An Unusual Case of Spontaneous Reactivation of Hepatitis B in Adult T-Cell Lymphoma/Leukemia

INTRODUCTION: Reactivation of hepatitis B (HBV) is typically triggered by immunosuppressive therapy of cancer, autoimmune disease, or organ transplantation. Here we report a rare case of spontaneous reactivation of hepatitis B in a patient newly diagnosed with adult T-cell lymphoma/leukemia without any exposure to immunosuppressive therapy of cancer. CASE DESCRIPTION/METHODS: A 34-year-old African American male was transferred from an outside institution for further management of probable T-cell lymphoma/leukemia as severe lymphocytosis was initially noted. Presenting symptoms included weakness and fatigue as well as bilateral conjunctival redness. His abdomen was mildly distended, and hepatomegaly was noted. Of interest, he was found to have elevated liver function tests (LFTs) and hepatitis panel showed acute hepatitis B with bloodwork significant for positive hepatitis B surface antigen, negative hepatitis B surface antibody, negative hepatitis B core IgM, positive hepatitis B core antibody and hepatitis B viral load of 16,954. Labs for hepatitis A and C were negative. He denied any known risk factors for hepatitis. Abdominal imaging showed peripancreatic concern of mass or swelling, mild hepatomegaly, splenomegaly and marked lymphadenopathy in the celiac, perigastric, pancreatic and aortocaval regions. Of note, he has not been on any immunosuppressive therapy or steroids prior to hospital admission. On hospitalization day #5, he was started on tenofovir and subsequently liver function tests continued to improve. He was also started on IV Solu-Medrol 1 g per day for 3 days with IV hydration and oral allopurinol. He continued to undergo diagnostic work-up as per hematology and Oncology prior to starting chemotherapy. On the day of discharge (day #17), remarkable improvement in his LFTs was noted. He was seen in GI clinic about 3 weeks later and his hepatitis B viral load was 760 and ALT was within normal limits. DISCUSSION: HBV reactivation is common following chemotherapy and is associated with a high mortality, however spontaneous HBV reactivation in the absence of cancer chemotherapy or transplantation is a rare clinical entity. Adult T-cell lymphoma/leukemia likely contributes to immune suppression or alteration in immune function causing spontaneous HBV reactivation. This case highlights the importance of screening all patients who are to undergo cancer chemotherapy, marked immunosuppressive treatments or solid organ or bone marrow transplantation for evidence of ongoing or previous hepatitis B.

2221 A Case of Rare Escape Mutation Type G130N and Conundrum of Heptitis B Serology

INTRODUCTION: Hepatitis B (HB) virus is a global public health problem as it affects more than 300 million patients around the world. It's well known that once we have Anti-HBs, seroconversion takes place, and that's a marker of viral clearance and immunity. In view of their important protective role, occurrence of anti-HBs and HBsAg is perplexing. Although this has been reported in 5-20% of cases of Chronic Hep B, it remains a confusing finding to many physicians who are unaware of the existence, explanation and implications of this finding. Herein, we will present a case of such a pattern. CASE DESCRIPTION/METHODS: A 49-year-old male with diabetes and hypertension was found to have elevated liver enzymes on routine blood work. Further workup resulted in diagnosing chronic hepatitis B. The patient’s viral serology results were positive for HB core antibody, HB surface antibody, HB surface antigen, HB e antigen, and a viral load of 1,500,000 IU/ml. Liver enzymes were elevated with ALT of 250U/L and AST of 180U/L. No masses were detected on liver ultrasound. Blood sample was sent to Center for Disease Control and analysis revealed a mutation G130N within the major hydrophilic region of surface antigen. The patient was started on Entecavir. After 12 months, the VL became undetectable. Serology was still positive for both HB s Ag and Ab but he successfully achieved HB e Ab +ve status. Liver enzymes normalized. DISCUSSION: The expected pattern in chronic HB is the presence of HBsAg and lack of anti-HBs. The mechanism underlying the coexistence of HBsAg and anti-HBs remains unclear. Mutations in the viral DNA were initially suggested by researchers to explain how the subtypes of the HBsAg and anti-HBs were heterologous. It was shown that there is a relation between this special serological profile and mutations in S gene region, particularly in the 'a' determinant of the major hydrophilic region of the surface antigen, including one located at G130N. Aside from mutations in the S gene region, the presence of heterologous subtype-specific antibodies, superinfection with a new HB strain, occult HB reactivation and false positivity for anti-HBs are other possible explanations. These patients might harbor an augmented HBV replicative capacity and HBV reactivation upon receiving immunosuppression. Antiviral prophylaxis must be considered before starting immunosuppressive drugs. It was also reported that coexistent HBsAg and anti-HBs independently increased the risk of advanced fibrosis and hepatocellular carcinoma.

Hepatitis B Virus Mutant Infections in Hemodialysis Patients: A Case Series

Rationale & ObjectiveHepatitis B virus (HBV) transmission in hemodialysis units has become a rare event since implementation of hemodialysis-specific infection control guidelines: performing hemodialysis for hepatitis B surface antigen (HBsAg)-positive patients in an HBV isolation room, vaccinating HBV-susceptible (HBV surface antibody and HBsAg negative) patients, and monthly HBsAg testing in HBV-susceptible patients. Mutations in HBsAg can result in false-negative HBsAg results, leading to failure to identify HBsAg seroconversion from negative to positive. We describe 4 unique cases of HBsAg seroconversion caused by mutant HBV infection or reactivation in hemodialysis patients.Study DesignFollowing identification of a possible HBsAg seroconversion and mutant HBV infection, public health investigations were launched to conduct further HBV testing of case patients and potentially exposed patients. A case patient was defined as a hemodialysis patient with suspected mutant HBV infection because of false-negative HBsAg testing results. Confirmed case patients had HBV DNA sequences demonstrating S-gene mutations.Setting & ParticipantsCase patients and patients potentially exposed to the case patient in the respective hemodialysis units in multiple US states.Results4 cases of mutant HBV infection in hemodialysis patients were identified; 3 cases were confirmed using molecular sequencing. Failure of some HBsAg testing platforms to detect HBV mutations led to delays in applying HBV isolation procedures. Testing of potentially exposed patients did not identify secondary transmissions.LimitationsLack of access to information on past HBsAg testing platforms and results led to challenges in ascertaining when HBsAg seroconversion occurred and identifying and testing all potentially exposed patients.ConclusionsMutant HBV infections should be suspected in patients who test HBsAg negative and concurrently test positive for HBV DNA at high levels. Dialysis providers should consider using HBsAg assays that can also detect mutant HBV strains for routine HBV testing.

Epigenetic modification and regulation of HBV cccDNA

Hepatitis B virus (HBV) infection, which can cause acute or chronic viral hepatitis, hepatic fibrosis, cirrhosis, and carcinoma (HCC), is a major global health problem. After the virus enters a hepatocyte, its genome translocates into the cell nucleus and forms covalently closed circular DNA (cccDNA). HBV cccDNA binds with histones and nonhistone proteins, forming an episomal minichromosome, which underlies the molecular basis of HBV infection persistence and reactivation after antiviral treatment. The term “epigenetics” traditionally refers to heritable traits without changes in DNA sequence, but it also describes general studies of chromatin biology. Increasing evidence suggests that the epigenetic regulation of cccDNA is closely related to viral replication and the outcome of chronic HBV infection. In this review, we mainly discuss the following two mechanisms underlying epigenetic regulation: DNA methylation and histone modification. DNA methylation usually occurs in the CpG dinucleotides; it is mediated by DNA methyltransferases (DNMTs) and is generally associated with transcriptional silencing. There are three predicted CpG islands in the HBV genome. CpG island 1 is rarely methylated, the methylation of CpG island 2 leads to reduced viral 3.5 kb RNA transcription and DNA replication, and the methylation of CpG island 3 is significantly correlated with hepatocarcinogenesis. The exact roles that DNMTs play in HBV DNA methylation have not been completely elucidated. The most studied histone modifications are histone acetylation and methylation. Histone acetylation, which is generally associated with transcriptional activation, is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone methylation, which is associated with both transcriptional activation and repression, is controlled by histone methyltransferases (HMTs) and histone demethylases (HDMs). Some of these enzymes, such as p300/CBP, HDAC1 and PRMT5, have been reported to participate in the epigenetic regulation of HBV cccDNA. Viral proteins are also involved in the epigenetic regulation of HBV cccDNA. HBV core protein (HBc) is a structural protein in the HBV capsid. It has been reported that HBc can be recruited to cccDNA, preferentially binding to CpG island 2. In addition, relative abundances of HBc binding are negatively associated with DNA methylation levels in CpG island 2, which suggests that HBc may be an epigenetic regulatory factor of HBV. HBx is a significant HBV regulatory protein and can also be recruited to cccDNA. In the presence of HBx, transcriptional activation factors such as p300/CBP and GCN5/PCAF are recruited to cccDNA and hyperacetylate the cccDNA-bound histones. This results in an open configuration of the viral minichromosome with higher transcriptional activity. In the absence of HBx, cccDNA-bound HATs are severely impaired, while HDACs and other transcriptional restriction factors are recruited to cccDNA, leading to a tight structure of the minichromosome with lower transcriptional activity. In this review, we summarize the development of epigenetic therapies involving existing and emerging epigenetic drugs and their potential applications in chronic HBV infection and HBV-related HCC. In addition, we describe current techniques and systems for research on cccDNA epigenetic regulation. The discovery that epigenetic regulators play important roles in the persistence of HBV and are potential therapeutic targets has presented a myriad of opportunities to treat or even cure HBV.

2302 A Case of Hepatitis B Reactivation Resulting in Fulminant Hepatic Failure

INTRODUCTION: Patients with chronic HBV/HIV coinfection are at high risk of HBV chronicity and reactivation. Here we present a case of a patient who presented with acute liver failure secondary to hep B reactivation after adjustment of his HIV medication regimen. CASE DESCRIPTION/METHODS: A 56 year old male with HIV/HBV coinfection with undetectable viral loads was evaluated in the ED for new onset nausea and jaundice. Examination was significant for jaundice in the absence of any encephalopathy or other stigmata of chronic liver disease. Blood tests revealed INR 3, ALK-P 210, ALT 2186, AST 2934 and Bili T/D 25.6/17, platelet count 197K, Cr 1.98, and CD4 count 394. Liver US showed normal hepatic echotexture with patent vasculature. Serologic evaluation showed undetectable HIV viral load, negative Hep C PCR, positive HepBsAg, and highly positive hepatitis B DNA (>1 billion copies). About 5 months prior to this acute presentation, he was switched from (Cobicistat, Elvitegravir, Emtricitabine, and Tenofovir) to another regimen that doesn’t include hepatitis B coverage (Atazanavir, Cobicistat , Rilpivirine, and Abacavir) due to concerns about Tenofovir contributing to his unexplained CKD. He was started on dual therapy with tenofovir and entecavir and was transferred to a nearby liver transplant center. His passed away after a short complicated hospital stay with acute liver failure and colonic pneumatosis. DISCUSSION: Our patient presented with acute fulminant liver failure after a brief period of inadvertent Hep B treatment interruption. Medical treatment was not helpful despite attempts at combination therapy with Tenfovovir and Entecavir (in contrast to Tenofovir monotherapy) despite the scarcity of data in this specific situation. There are case reports that demonstrated clinical improvement especially early treatment in the course; however progression to hepatic failure, liver transplantation, and death has also been widely reported despite therapy. This case serves as a reminder to all medical providers about the complexity of concomitant chronic HBV and HIV coinfection. Any medication regimen change in this patient population needs a multidisciplinary team based approach between HIV specialists and Hepatologists.

767 Inflammatory Bowel Disease Patients Prior to Starting on Anti-TNF Are Over 5 Times More Likely to Be Screened for Hepatitis B Infection Compared to Those Starting High Dose Corticosteroids

INTRODUCTION: Screening for hepatitis B virus (HBV) infection in inflammatory bowel disease (IBD) patients prior to initiating anti-tumor necrosis factor alpha (anti-TNF) therapy has significantly improved over the past decade. HBV screening prior to initiating high dose corticosteroids (HDC) is largely unknown despite potentially greater risks of HBV reactivation compared to anti-TNF. This study aims to determine the factors associated with HBV screening and whether the type of immunosuppression affects screening practices. METHODS: This retrospective chart review included Veterans with diagnostic codes for Crohn's Disease (CD: ICD-9-CM 555.x and ICD-10-CM K50.x) and ulcerative colitis (UC: ICD-9-CM 556.x and ICD-10-CM K51.x) first recorded between 01/2013 to 08/2016 at the Cleveland Veterans Affairs Medical Center. IBD patients who were started on anti-TNF or HDC were assessed whether HBV screening was conducted within 12 months of initiating therapy. HDC was defined as ≥10 mg for ≥4 consecutive weeks. Patient factors including gender, age, race, service connectivity (SC), and type of immunosuppression were assessed as independent predictors for screening. RESULTS: Among 571 Veterans, 56 started immunosuppression with 17 on anti-TNF and 39 on HDC. A total of 31/56 (56%) were screened: 90% male, mean age 49, 32% mean SC, 45% on anti-TNF and 55% on HDC. A total of 25/56 (44%) were not screened: 96% male, mean age 58,17% mean SC, 12% on anti-TNF and 88% on HDC. In those on anti-TNF, 88% were screened compared to 44% on HDC (P = 0.007). In multivariate analysis, immunosuppression type was significantly associated with screening where patients initiated on anti-TNF were 5.5 times more likely to be screened compared to those on HDC (OR 0.18, P = 0.025). Age, gender, race, and service connectivity did not have any impact on screening. CONCLUSION: Overall, 56% of IBD patients receiving immunosuppression were screened for HBV. 88% were screened prior to anti-TNF compared to 44% prior to HDC. Patients initiated on anti-TNF were over 5 times more likely to be screened compared to those on HDC. Importance of HBV screening prior to high dose corticosteroids in IBD patients should be emphasized in societal guidelines and clinical practice, given that HDC poses a potentially greater risk of HBV reactivation compared to a biologic.

3191 Two Cases of False Positive Hepatitis B Surface Antigen With Positive Hepatitis B E-Antigen

INTRODUCTION: Hepatitis B surface antigen (HBsAg), is a HBV surface protein particle that indicates current HBV infection. Hepatitis B e Ag (HBeAg) indicates active HBV replication. HBsAg, is a sensitive test, that utilizes anti-HBs to bind to and detect surface antigens to HBV. Any weakly positive HBsAg test needs to be further confirmed using a neutralization test to confirm infection. Below we have briefly described two cases of unusual hepatitis B serology. CASE DESCRIPTION/METHODS: Case 1- 78-year-old Caucasian male, with CKD, was worked up for hepatitis B as he was being considered for dialysis. Initially, on history he had provided positive risk factors (use of illicit drugs and multiple sexual partners) for hepatitis B infection. He denied any recent vaccinations. The transaminases were within normal limits. The hepatitis B surface antigen (HBsAg) was positive. However, the neutralization test was not confirmatory on two occasions. He had hepatitis B e Ag (HBeAg) positive as well. He was negative for Hepatitis B surface antibody (HBs Ab), hepatitis B core total antibody (AntiHBc-T), hepatitis B core IgM (AntiHBc- IgM) and HBV e antibody (anti-HBe). The hepatitis B viral DNA was also negative. The patient was negative for hepatitis C and HIV. The results were similar 6 months later. Case 2- 65-year-old Caucasian male, with psoriatic arthritis, was screened for hepatitis B as part of his management for psoriatic arthritis and was found to have a reactive HBsAg. He had no defined risk factors for HBV. His initial HBsAg was negative 7 years back. His hepatitis B serological profile was similar to the first patient. DISCUSSION: Heterophile antibodies could explain why the confirmatory test for HBsAg, after neutralization, was negative. Our patient had not received the HBV vaccination. Also, it does not explain why the HBeAg would be positive. HBsAg “escape” mutants are generally considered when the HBeAg and/or the HBV DNA is positive, in chronic HBV infection, which was not our case. Though we have come a long way in improving diagnostic laboratory capabilities, we still require better assays to accurately diagnose HBV. Present HBV guidelines do not define our case. We were unable to identify similar case reports. We continue to monitor our two patients, for if we decide to start them on hemodialysis (our first patient) or initiate immunosuppressive agents (for our second patient), the challenges of HBV reactivation are real.

Clinical Practice Guidance for Management of Anti HBc Positive Patients

Hepatitis B core antibody (Anti HBc) is currently considered the most sensitive serological marker for a patient’s history of hepatitis B virus (HBV) infection given its long-term persistence in the bloodstream. The serological pattern of isolated Anti HBc (IAHBc) has been of clinical interest over the past several years.,Thegrowing data of IAHBcsuggestingit as a marker for occult HBV infection (OBI). Occult HBV infection defined as HBV DNA detection in serum or the liver by sensitive diagnostic tests in HBsAg negative individuals with or without serologic markers of previous viral exposure. OBI is especially concerned in blood transfusion (BT), organ donation and reactivation of HBV infection following immunosuppressive therapy. HBV reactivation depends on viral and host factors. The important clinical implications of IAHBcis in the setting of co-infection with hepatitis C virus (HCV), reactivation risk of HBV during directly acting anti viral (DAA) therapy in HCV infection which may lead to progression of liver disease and hepatocellular carcinoma (HCC). Antiviral prophylaxis has been recommended in moderate to high risk of reactivation prior to immunosuppressive and biologics. The main goal of therapy is to improve survival and quality of life by preventing disease progression and to prevent consequent development of HCC. It is proposed to perform Anti-HBc test as a screening test prior to blood transfusion, HBVvaccination, DAA and immunosuppressive therapy in addition to HBsAg screening test.
 J Bangladesh Coll Phys Surg 2019; 37(4): 196-201