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Antibody Levels and Protection after Hepatitis B Vaccine: Results of a 30 year Follow-up Study and Response to a Booster Dose

Michael Bruce1, Dana J. Bruden1, Debby Hurlburt1, Carolyn Zanis1, Gail C. Thompson1, Lisa D. Rea1, Michele Toomey1, Lisa J. Townshend-Bulson2, Karen Rudolph1, Lisa Bulkow1, Philip Spradling3, Richard Baum1, Thomas W. Hennessy1, Brian J. McMahon2
1Arctic Investigations Program,Centers for Disease Control and Prevention, Anchorage, AK; 2Liver Disease and Hepatitis Program,, Alaska Native Tribal Health Consortium, Anchorage, AK; 3Epidemiology and Surveillance Branch', Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA

Background. The duration of protection in children and adults resulting from hepatitis B vaccination is unknown. In 1981, after licensure of hepatitis B vaccine in the United States, we immunized a cohort of 1578 Alaska Native adults and children from 15 Alaska villages who were 6 months or older using 3 doses of plasma-derived hepatitis B vaccine. We performed yearly serologic testing for 11 years, and at 15 years. At 22 years, we performed serologic testing on participants living in 7 villages and administered a hepatitis B booster dose to persons with antibody to hepatitis B surface antigen (anti-HBs) <10 mlし/ml. To determine the protection afforded by hepatitis B vaccine, Alaska Native persons who had received plasmaderived hepatitis B vaccine were tested for anti-HBs levels 30 years after receiving the primary series. Methods. Those with levels <10 mlU/ml received 1 dose of recombinant hepatitis B vaccine 2-4 weeks later and were then evaluated on the basis of anti-HBs measurements 30 days post-booster. Objectives: At 30 years after vaccination: 1)Determine the proportion of persons with protective anti-HBs levels (> 10 mIU/ml), 2) Evaluate response to a booster dose among persons with antibody levels <10 mlU/ml, 3) Compare characteristics of persons with and without protective antibody levels. Results. 〇f 433 participants, 63 (14%) had received a booster dose at 22 years (Group 1), 129 (30%) did not receive a booster dose at 22 years (because their anti-HBs levels were > 10 mlU/ml, Group , and 241(56%) persons did not participate in the 22 year study (Group 3). Among participants in Groups 1, 2 and 3: 9 (14%), 85 (66%), and 123 (51%) had an anti-HBs level > 10 mlU/ml, respectively. A booster dose was administered to Group 2 and 3 participants with anti-HBs levels <10 mlU/ml according to study protocol. Among Group 2 and 3 participants who were available for follow-up, 33/36 (92%) and 75/85 (88%), responded to a booster dose with an anti-HBs level > 10 mIU/ml at 30 days, respectively. Initial anti-HBs level after the primary series was correlated with higher anti-HBs levels at 30 years. Based on the 241 Group 3 persons, including persons at 30 years with an anti-HBs level > 10 mlU/ml and potential booster recipients of whom 88% were predicted to respond to the booster dose,, we estimate > 90% of participants were protected. No symptomatic acute or chronic hepatitis B virus infections were identified during the 30 year follow-up. Conclusions. The protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 30 years. Booster doses are not needed.

Disclosures:

The following people have nothing to disclose: Michael Bruce, Dana J. Bruden, Debby Hurlburt, Carolyn Zanis, Gail C. Thompson, Lisa D. Rea, Michele Toomey, Lisa J. Townshend-Bulson, Karen Rudolph, Lisa Bulkow, Philip Spradling, Richard Baum, Thomas W. Hennessy, Brian J. McMahon

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Reduction in eGFR in patients with chronic hepatitis B. An analysis of the Italian Master-B cohort

Giuseppino Brancaccio1, Alessandra Nardi2, Salvatore Madonia3, Massimo Fasano4, Pietro Andreone5, Marco Massari6, Gianluca Svegliati Baroni7, Barbara Coco8, Alfredo Marzano9, Enzo Petrelli10, Gioacchino Angarano11, Caius Gavrila2, Giovanni B. Gaeta1
1Infectious Diseases, Second University, Naples, Italy; 2Mathematics, University Tor Vergata, Rome,. Italy; 3Internal Medicine, University, Palermo, Italy; 4Infectious Diseases, University, Foggia, Italy; 5Internal Medicine, University, Bologna, Italy; 6Infectious Diseases, Hospital, Reggio Emilia, Italy;7Gastroenterology, University, Ancona, Italy; 8Gastroenterology, University, Pisa, Italy; 9Gastroenterology, Molinette Hospital, Turin, Italy; 10Infectious Diseases, Hospital, Pesaro, Italy; 11 Infectious Diseases, University, Bari, Italy

Background: Patients with chronic hepatitis B often present a reduction in Glomerular Filtration Rate (GFR) which requires an adaptation of the dose of antiviral drugs. There is still some degree of uncertainty on the prevalence and causes of this condition. Methods: The Master-B study is a prospective, observational cohort that enrolled consecutive HBsAg positive patients seen in 75 Italian centers from June 2009 to December 2011, irrespective of liver disease or therapy. In this analysis we present the eGFR calculated at baseline using the MDRD formula. The analysis was performed using SAS software. Continuous variables were described by their mean, median, standard deviation, categorical variables as frequencies. Associations between categorical variables were evaluated by chi squared test or Fisher exact test. Differences in expected values of continuous covariates were compared by t-test or Wilcoxon test. Results: Data were available in 2105 patients out of the 2916 enrolled in the study. The median age was 51.3 years, 71% were males; cirrhosis was present in 24.5% of the cases; 50% of the patients were receiving an antiviral therapy. eGFR(mL/min) value was 95.2 ± 27.8 in patients without cirrhosis and 90.3 ± 27.2 in patients with cirrhosis (p<0.0001) and was correlated with age (r=0.39 and 0.41, respectively; Figure); a value below 60 was recorded in 5.3% and 11.2%, respectively, in the two groups (p<0.0001). At univariate analysis eGFR was associated with age, gender, cirrhosis and exposure to adefovir/tenofovir. At multivariate analysis only age and cirrhosis were associated with reduction in eGFR. Conclusions: In this large series of patients with chronic hepatitis B a reduction in eGFR below 60 mL/min occurred in less than 10% of the patients and was associated with age and cirrhosis but not with antiviral therapy.

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Disclosures:

Pietro Andreone - Advisory Committees or Review Panels: Roche, Janssen-Cilag, Gilead, MSD/Schering-Plough; Grant/Research Support: Roche, Gilead; Speaking and Teaching: Roche, MSD/Schering-Plough

Giovanni B. Gaeta - Advisory Committees or Review Panels: Janssen, Merck, Boheringer Ing; Board Membership: Novartis; Speaking and Teaching: BMS, Gilead, Roche, MSD

The following people have nothing to disclose: Giuseppina Brancaccio, Alessandra Nardi, Salvatore Madonia, Massimo Fasano, Marco Massari, Gianluca Svegliati Baroni, Barbara Coco, Alfredo Marzano, Enzo Petrelli, Gioacchino Angarano, Caius Gavrila

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Reduction of hepatocellular carcinoma in hepatitis Brelated cirrhosis patients with long-term entecavir therapy - An interim report of C-TEAM study

Tung-Hung Su1, 18, Tsung-Hui Hu2, Chun-Che Lin3, Cheng-Yuan Peng4, Wan-Long Chuang5, Chi-Yi Chen6, Chia-Chi Wang7, RongNan Chien8, Yi-Hsiang Huang9, Chih-Lin Lin10, Sheng-Shun Yang11, Yi-Wen Huang12, Shih-Jer Hsu13, Horng-Yuan Wang14, Lein-Ray Mo15, Bair Ming-jong16, Cheng-Chao Liang17, Tai-Chung Tseng7, Chi-Ling Chen18, Yung-Chao Lei19, Jia-Horng Kao1, 18
1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Division of Gastroenterology, Department of Infernal Medicine, Chung Shan Medical University Hospital, Taichung, Toiwon; 4Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 5Department of Internal Medicine,, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung, Taiwan; 6Department of Internal Medicine, Chia-Yi Christian Hospital, Chia-Yi, Taiwan; 7Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan; 8Liver Research Unit, Chang Gung Memorial Hospital, Keelung, Taiwan; 9Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 10Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan; 11Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 12Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan; 13Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin County, Taiwan; 14Division of Gastroenterology and Hepotology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 15Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; 16Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan; 17Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 18Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; 19Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

Background A previous CALM-study showed lamivudine marginally reduces hepatocellular carcinoma (HCC) risk in patients with advanced fibrosis or cirrhosis. Whether a more potent drug with least drug resistance profile could further reduce HCC risk remains unclear. We thus aimed to investigate the reduction of HCC in hepatitis B-related cirrhosis patients with long-term entecavir therapy. Materials and Methods In the C-TEAM (Cirrhosis Taiwanese Entecavir Multicenter) study, we enrolled HBVrelated compensated cirrhosis patients without antiviral treatment during 1985-1995 (historical control group) and those who received long-term entecavir monotherapy since 2008 (treatment group). All patients had baseline serum HBVDNA level > 2, 000 IU/mL and were followed longitudinally for clinical outcomes including cirrhotic complications and HCC development. Results As of March 31st, 2013, we enrolled 1 patients in the no-treatment group and 666 in the treatment group from 1 7 academic centers. The gender and baseline HBeAg status levels were comparable between these two groups. Compared to historical controls, treated patients were significantly older and had more advanced liver diseases. The mean duration of follow-up was 9.1 and 2.7 years in the notreatment and treatment groups, respectively. In the first 2.7 years of follow-up, there were 16 (2.4%) newly developed HCC in the treatment group and 32 (5.2%) in the no-treatment group (P=. 009). The HCC incidence rate was 0.014 (per per-son-year) in the no-treatment group and 0.009 (per personyear) in the treatment group. A 2.7-year entecavir monotherapy was associated with 59% reduction of lifetime HCC risk (adjusted hazard ratio: 0.41, 95% CI: 0.20-0.84) in compensated cirrhosis patients. [Figure] Conclusion Prolonged entecavir therapy may reduce HCC development in hepatitis B-related compensated cirrhosis patients and a longer term follow-up is required to see its impact on cirrhotic complications.

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Disclosures:

Wan-Long Chuang - Advisory Committees or Review Panels: Gilead, Roche, Norvatis; Speaking and Teaching: BMS

Yi-Wen Huang - Grant/Research Support: GSK; Speaking and Teaching: Roche, Bristol-Myers Squibb, GSK

The following people have nothing to disclose: Tung-Hung Su, Tsung-Hui Hu, Chun-Che Lin, Cheng-Yuan Peng, Chi-Yi Chen, Chia-Chi Wang, Rong-Nan Chien, Yi-Hsiang Huang, Chih-Lin Lin, Sheng-Shun Yang, Shih-Jer Hsu, Horng-Yuan Wang, Lein-Ray Mo, Bair Ming-jong, Cheng-Chao Liang, Tai-Chung Tseng, ChiLing Chen, Yung-Chao Lei, Jia-Horng Kao

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Risk and risk factors of hepatocellular carcinoma (HCC) in Caucasian chronic hepatitis B (CHB) patients with or without cirrhosis treated with entecavir (ETV) or tenofovir (TDF)

George V. Papatheodoridis1, George N. Dalekos2, Cihan Yurdaydin3, Ioannis Goulis4, Pauline Arends5, Maria Buti6, Vana Sypsa7, Spilios Manolakopoulos1, Giampaolo Mangia8, Nikolaos Gatselis2, Onur Keskin3, Savvoula Savvidou4, Bettina E. Hansen5, Christos Papaioannou1, Kostas Galanis2, Ramazan Idilman3, Massimo Colombo8, Rafael Esteban6, Harry L. Janssen5, 9, Pietro Lampertico8
12nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece; 2Department of Infernal Medicine, Thessalia University Medical School, Larissa, Greece; 3Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey; 44th Department of Internal Medicine, Aristotle University of Thessaloniki Medical School, Thessaloniki, Greece; 5Department of Gastroenterology & Hepatology, ErasmusMC, Rofferdom, Netherlands; 6Hospital General Universitario Valle Hberon and Ciberehd, Barcelona, Spain; 7Department of Hygiene, Epidemiology & Medical Statistics, Athens University Medical School, Athens,Greece; 81st Division of Gastroenterology, Fondazione IRCCS Cá GrandaOspedale Maggiore Policlinico,Universitá degli Studi di Milano, Milano, Italy; 9Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada

Background/Aims: HCC may still develop in patients under lamivudine (LAM) with or without adefovir rescue therapy, while the HCC risk under newer nucleos(t)ide analogues (NAs) is unclear, particularly in Caucasian patients. We evaluated the incidence and risk factors of HCC in a large, multicenter, cohort of predominantly Caucasian CHB patients treated with ETV or TDF. Methods: We included 1231 adult CHB patients (mean age 52±15 years, males 72%, Caucasians 98.5%) treated with ETV/TDF (ETV: 530, TDF: 369, TDF+LAM: 307, TDF+ETV: 25) for ≥12 months in 7 Hepatology centers. 664 (54%) were NAs naive [(Peg)IFN in the past: 171], 433 (35%) had prior NAs resistance [(Peg)IFN: 142) and 134 (11%) were NA(s) exposed without resistance [(Peg)IFN: 16]. CHB without cirrhosis, compensated and decompensated cirrhosis were diagnosed in 780 (66%), 359 (30%) and 43 (4%) cases (disease severity unclassified: 49). The predictability of baseline parameters and REACH-B (Lancet Oncol 2011; 12: 568-74) and GAG-HCC (J Hepatol 2009; 50: 80-8) scores was assessed. Mean follow-up was 39±17 months. Results: HCC developed in 52/1231 (4.2%) patients at a median of 17 (range: 2-58) months after ETV/TDF onset. The cumulative 1-, 3-, 5-year HCC rates were higher in decompensated (11.6%, 23.8%, 29.7%) than compensated cirrhosis (2.5%, 5.8%, 20.9%) than CHB (0.8%, 1.2%, 2.5%) (log-rank: p<0.001 for all comparisons). In univariate analyses, the HCC risk was significantly associated with older age (HR/year: 1.07, p<0.001), lower platelets (HR/1000/mm3: 0.98, p<0.001), higher REACH-B (HR/unit: 1.13, p=0.022) or GAG-HCC score (HR/unit: 1.05, p<0.001) and relatively associated with male gender (HR: 2.05, p=0.062), higher BMI (HR/kg/m2: 1.07, p=0.052) and no history of (Peg)IFN (HR: 2.06, p=0.050), while it was not associated with country or center, past NAs exposure, prior resistance, baseline ALT, HBV DNA, HBeAg status, ETV or TDF, and on-therapy virological responses. HCC risk was associated with both REACH-B (p=0.030) and GAG-HCC score (p<0.001) in cirrhotics, but only with GAG-HCC score (p=0.035) in non-cirrhotics. In multivariate analyses, the HCC risk was independently associated only with lower platelets (HR/1000/mm3: 0.98, p=0.005) in non-cirrhotics and with older age (HR/year:

1.05, p=0.012), liver decompensation (HR: 2.78, p=0.019) and past NAs exposure (HR: 0.47, p=0.050) in cirrhotics. Conclusions: Data from this large mutlicenter study in predominantly Caucasian patients indicate that the HCC risk remains increased in ETV/TDF treated CHB patients, particularly those with advanced disease. The applicability of HCC risk scores developed in Asians seems to be modest in Caucasian CHB patients.

Disclosures:

George V. Papatheodoridis - Advisory Committees or Review Panels: Merck, Novartis, Abbvie, Boerhinger, Bristol-Meyer Squibb, Gilead, Roche, Janssen; Grant/Research Support: Roche, Gilead, Bristol-Meyer Squibb; Speaking and Teaching: Merck, Bristol-Meyer Squibb, Gilead, Roche, Janssen

Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche, Merck, Gilead

loannis Goulis - Consulting: MSD, Gilead Sciences, Novartis, Janssen-Cilag; Grant/Research Support: BMS, Roche; Speaking and Teaching: BMS, MSD, Gilead Sciences, Novartis, Janssen-Cilag, Roche

Maria Buti - Advisory Committees or Review Panels: Boerhinger Inghelm, Boerhinger Inghelm; Speaking and Teaching: MSD, Bristol-Myers Squibb, Novartis, Gilead, Janssen, MSD, Bristol-Myers Squibb, Novartis, Gilead, Janssen

Spilios Manolakopoulos - Advisory Committees or Review Panels: NOVARTIS, ROCHE, MSD, BMS, GILEAD; Consulting: ROCHE, GILEAD, BMS; Speaking and Teaching: MSD, GILEAD, BMS

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERSSQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOLMEYERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX

Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo, MSD, BMS, Novartis, Gilead, Glaxo, Janssen

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

The following people have nothing to disclose: George N. Dalekos, Pauline Arends, Vana Sypsa, Giampaolo Mangia, Nikolaos Gatselis, Onur Keskin, Savvoula Savvidou, Bettina E. Hansen, Christos Papaioannou, Kostas Galanis, Ramazan Idilman

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Immune correlates of chronic hepatitis B phenotypes in North America: Results from the Hepatitis B Research Network (HBRN)

Jang-June Park1, David K. Wong2, Abdus S. Wahed3, William M. Lee4, Jordan J. Feld2, Norah Terrault5, Mandana Khalili5, Kris V. Kowdley6, Daryl Lau7, Richard K. Sterling8, W. Ray Kim9, Coleman Smith10, Robert L. Carithers11, Danielle L. Levine1, James Keith1, Mary E. Valiga1, Anna S. Lok12, Kyong-Mi Chang1
1Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA; 2Division of Gastroenterology, University of Toronto, Toronto, ON, Canada; 3Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA; 4Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; 5Division of Gastroenterology, University of California San Francisco, San Francisco, CA; 6Center for Liver Disease, Virginia Mason Medical Center, Seattle, WA; 7Division of Gastroenterology, Harvard Medical School, Boston, MA; 8Division of Gastroenterology, Virginia Commonwealth University, Richmond, VA; 9Division of Gastroenterology, Mayo Clinic, Rochester, MN; 10Division of Gastroenterology, University of Minnesota, Twin Cities, MN; 11Department of Medicine, University of Washington Medical Center, Seattle, WA; 12Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI

Participants with chronic hepatitis B (cHBV) are phenotypically classified as immune active (IA), immune tolerant (IT) or inactive carriers (IC) based on clinical parameters such as serum ALT and HBV DNA levels observed over time. These clinical cHBV phenotypes are relevant for therapeutic decision-making and prognosis. In this study, we investigated if specific immune effector and regulatory response patterns define pathogenetically relevant immune signatures for the cHBV phenotypes. Methods: 165 participants (46 HBeAg+ IA, 62 HBeAg- IA, 18 IT and 39 IC) were recruited for immune analyses between Feb 2011-Dec 2012 from 10 North American liver centers within the NIDDK-funded Hepatitis B Research Network. cHBV phenotypes were assigned based on historical data and compared to those based on HBeAg, HBV DNA and ALT values at the time of immune analysis. Antiviral T cell effector and regulatory responses were examined by proliferation and IFNγ/IL10 ELISPOT assays, with peripheral blood lymphocytes stimulated with overlapping peptides from HBV preS/S, pre-C/C and polymerase, plus Flu and PHA controls. Further immune regulatory and activation markers were examined by multi-color flow cytometry. Results: The 165 cHBV participants included 82% Asians and 48% females with median age 43 years, ALT 36 U/L, HBV DNA 4.9 log IU/L, and mostly HBV genotypes B (46%) or C (32%). Notably, historically-defined phenotypes differed from those based on lab values at the time of immune analysis in 34% of participants. As for antiviral T cell response, HBV-specific effector T cell proliferation and IFNγ responses as well as regulatory IL10 responses were generally suppressed with no clear distinction between the cHBV phenotypes. However, HBeAg+ IA participants had higher %FoxP3+ regulatory T cells (Tregs) than IT (p=0.0085) or IC participants (p=0.023), with a positive association between %CD8 T cells and serum ALT level (R=0.56, p=0.001). Moreover, HBeAg- IA participants tended to show greater inhibitory programmed death-1 (PD-1) receptor expression in CD8 T cells, suggesting an apparent differential induction of global immune regulatory pathways among cHBV phenotypes. Conclusions: cHBV is associated with weak circulating antiviral effector and IL10+ regulatory T cell responses regardless of clinical phenotypes. Interestingly, the immune active rather than tolerant phenotype was associated with FoxP3+ Tregs and PD-1 induction, suggesting compensatory induction of inhibitory pathways in immune active cHBV with potential pathogenetic and therapeutic relevance. Studies are ongoing to better define the immune signatures for cHBV phenotypes and their evolution in the HBRN.

Disclosures:

David K. Wong - Grant/Research Support: Gilead, BMS, Vertex, BI

William M. Lee - Consulting: Eli Lilly, Novartis; Grant/Research Support: Gilead, Roche, Vertex, BI, Anadys, BMS, merck; Speaking and Teaching: Merck

Jordan J. Feld - Advisory Committees or Review Panels: Roche, Merck, Vertex, Gilead, Abbott, Tibotec, Theravance, Achillion; Speaking and Teaching: Merck, Roche, Abbott

Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Consulting: BMS; Grant/Research Support: Eisai, Biotest, Vertex, Gilead, AbbVie, Novartis

Mandana Khalili - Advisory Committees or Review Panels: Gilead Inc.; Grant/Research Support: Gilead Inc., BMS Inc, BMS Inc

Kris V. Kowdley - Advisory Committees or Review Panels: Abbott, Gilead, Merck, Novartis, Vertex; Grant/Research Support: Abbott, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex

Daryl Lau - Advisory Committees or Review Panels: Gilead, BMS; Consulting: Roche; Grant/Research Support: Gilead, Merck

Richard K. Sterling - Advisory Committees or Review Panels: Merck, Vertex, Salix, Bayer, BMS, Abbott; Grant/Research Support: Merck, Roche/Genentech, Pfizer, Medtronic, Boehringer Ingelheim, Bayer, BMS, Abbott

W. Ray Kim - Advisory Committees or Review Panels: Salix; Consulting: Bristol Myers Squibb, Gilead

Coleman Smith - Advisory Committees or Review Panels: Vertex, Gilead, Janssen; Grant/Research Support: Gilead, Abbvie, Janssen, Salix, BMS; Speaking and Teaching: Merck, Vetex, Gilead, Bayer/Onyx, BMS

Anna S. Lok - Advisory Committees or Review Panels: Gilead, Immune Targeting System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis; Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche

Kyong-Mi Chang - Stock Shareholder: BMS (spouse employment)

The following people have nothing to disclose: Jang-June Park, Abdus S. Wahed, Robert L. Carithers, Danielle L. Levine, James Keith, Mary E. Valiga

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Hepatitis B Virus (HBV) Reverse Seroconversion after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) and the Impact of Post-Transplant Vaccination

Sarah P. Hammond1, 2, Vincent T. Ho2, Chinweike Ukomadu3, Lindsey R. Baden1, Francisco M. Marty1, 2
1Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA; 2Dana-Farber Cancer Institute, Boston, MA; 3Division of Gastroenterology, Brigham and Womens Hospital, Boston, MA

Background: HBV reactivation in allogeneic HSCT recipients with evidence of resolved HBV pre-HSCT, also called ‘reverse seroconversion' (RS), is a significant clinical problem. Studies are limited by small cohort size and short follow up duration. We undertook this study in which we expand on a previouslyreported cohort to assess risk factors for RS and determine impact of HBV vaccination after HSCT. Methods: We retrospectively identified all allogeneic HSCT recipients with resolved HBV (core IgG+, surface antigen [HBsAg]-, HBV DNA undetectable) transplanted from 1/00 to 1/12.Medical records were reviewed. Follow up concluded 1/13.RS was defined as redevelopment of HBsAg positivity. Cox proportional hazard model was used to assess risk factors for RS in a time-dependent manner. Results: 100 patients with resolved HBV underwent allogeneic HSCT during the study. 67 (67%) were men. Median age was 52 (range 19-71). Median follow up was 28 months (range 1-130). 16 of 65 (25%) HSCT recipients who survived >1 year were vaccinated for HBV at median of 12 months (range 6-47) after HSCT. Subsequent HBV surface antibody (HBsAb) was measured in 7 of 16; median HBsAb after vaccination was 10 IU/ml (range <5-378). 17 (17%) developed RS at median of 20 months (range 2-47) after HSCT, including 2 who had been vaccinated. Median time to RS in vaccinated recipients was 38 months (range 20-47) vs. 24 (range 12-39) in non-vaccinated recipients who reactivated >1 year after HSUT (P = 0.15). In multivariate Cox regression model (that included covariates with P<0.05 in univariate analysis, see Table) pretransplant HBsAb<10 Iし/mL and extensive chronic graft-versus-host disease (cGVHD) were independent risks for RS. Additional bivariate analysis was performed to assess impact of post-HSCT vaccination while controlling for extensive cGVHD (reason for vaccine to be held). Post-HSCT vaccination was not associated with reduction in RS (aHR 0.43, Cl 0.10-1.89) while extensive cGVHD remained a significant risk (aHR 6.63, Cl 1.66-26.5). Conclusion: Pre-HSCT HBsAb and extensive cGVHD after HSCT are independent risks for RS. Post-HSCT HBV vaccination did not significantly reduce RS risk.

CovariateNUnivariate HR (CI)PMultivariate HR (CI)P
Male671.64 (0.53-5.04)0.39
Age 1.00(0.96-1.04)0.84
Pre-HSCT HBsAb <10134.64 (1.68-12.9)0.0034.24(1.53-11.8)0.006
Myeloablative Conditioning371.95 (0.75-5.06)0.17
Matched donor910.32(0.09-1.10)0.07
Related donor471.03 (0.40-2.67)0.95
Severe acute GVHD140 (0-oo)0.99
Extensive cGVHD436.57(1.65-26.1)0.0085.81 (1.39-24.4)0.02
HBV vaccination160.43 (0.10-1.90)0.27

Disclosures:

Sarah P. Hammond - Grant/Research Support: Merck Chinweike Ukomadu - Consulting: Gilead Sciences

The following people have nothing to disclose: Vincent T. Ho, Lindsey R. Baden, Francisco M. Marty