SEARCH

SEARCH BY CITATION

882

  1. Top of page

Resolution of Hepatitis B Virus (HBV) Infection is Common after Antiviral Therapy in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients who Develop Reverse Seroconversion

Sarah P. Hammond1,2, Vincent T. Ho2, Chinweike Ukomadu3, Lind-sey R. Baden1,2, 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 Women's Hospital, Boston, MA

Background: HBV reactivation in allogeneic HSCT recipients with evidence of resolved HBV infection before transplant (also called reverse seroconversion [RS]) is a significant clinical problem which can occur years after HSCT. Clinical outcomes of allogeneic HSCT recipients who developed RS are poorly described. We undertook this retrospective study to describe clinical outcomes among those who developed RS after HSCT. Methods: We identified all allogeneic HSCT recipients with evidence of resolved HBV infection (core IgG positive, surface antigen [HBsAg] negative, HBV DNA undetectable) before HSCT who were transplanted between 1 /00 and 12/11. HBV reactivation was defined as redevelopment of HBsAg positivity. Medical records were reviewed for clinical outcomes up to 5/13. Results: Of 100 allogeneic HSCT recipients with prior HBV infection 17 (17%) developed RS after HSCT. Cumulative probability of RS was 6.2%, 12.7%, 20.7% and 31.7% at 1, 2, 3 and 4 years after HSCT. Median ALT at RS diagnosis was 83 U/L (range 13–1411). Of 17 with RS 15 had HBV DNA >10^5 IU/mL and were treated with entecavir (14) or lamivu-dine/adefovir (1). Two patients that had HBV DNA <10^5 IU/mL were observed without antiviral therapy and cleared HBsAg within a month (13 and 28 days). Of the 15 patients who were treated, one developed symptomatic hepatitis after treatment started with transient jaundice and ascites which resolved on continued antivirals. 6 of 15 (40%) cleared HBsAg at a median of 17 months (range 1–52, IQR 8–28) after antiviral therapy started. Cumulative probability of clearing HBsAg was 15.4%, 32.3%, 40.8% and 55.6% after 1, 2, 3 and 5 years of antiviral therapy. Despite negative or low HBV surface antibody at time of reactivation, all 6 who cleared HBsAg developed robust quantitative surface antibody in conjunction with HBsAg clearance: median 336 IU/mL (range 98->1000). 5 of 6 who cleared HBsAg stopped antiviral therapy within 6 months of clearance and have been followed for a median of 54 months (range 22–66) without HBV recurrence; the remaining patient is on antiviral therapy for a planned 6 month course post HBsAg clearance. 5 of 17 patients died during follow up (29%), but none died of HBV complications; causes of death included relapsed cancer, graft-versus-host disease and mucormycosis. Conclusions: Allogeneic HSCT recipients with resolved HBV before HSCT are at prolonged risk for RS which makes prophylactic antiviral treatment unattractive. However, RS resulted in only one episode of symptomatic illness in this cohort. Furthermore, two recipients cleared HBsAg without antiviral therapy and among those who required treatment 40% cleared HBsAg durably.

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

883

  1. Top of page

Loss Of HBsAg Following Spontaneous Versus Treatment-Induced Clearance Of HBeAg In United States Patients With Chronic Hepatitis B

Adil Abdalla, Anthony Loria, Xiongce Zhao, Joni Trenbeath, T. Jake Liang, Jay H. Hoofnagle, Marc G. Ghany;
National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

Background: Understanding the natural history of chronic hepatitis B is important for counseling patients of prognosis and need for therapy. Aim: To investigate the natural history of chronic hepatitis B after loss of HBeAg by interrogating a database with 35 years follow-up focusing on HBsAg loss. Methods: From a database of 787 HBsAg-positive subjects spanning 1978 until 2013, 138 patients with either spontaneous (n=87) or treatment-related (n=51) (82% interferon, 18% oral nucleo-side) HBeAg loss and a minimum of 1 year follow-up with no intervening therapy were identified. Patients <18 years of age, those with HCV, HDV and HIV co-infection were excluded. The first date of a negative HBeAg result was used as the index time for calculation of time to events. Selected stored serum samples were retested for HBV DNA levels using COBAS Taqman HBV Assay (Roche). Baseline characteristics associated with the outcomes of HBsAg loss were assessed by ANOVA and multivariate stepwise logistic regression. Results: At baseline, the mean age of the 138 patients who lost HBeAg was 42 years; 66% were men; and 56% were white, 33% Asian, 10% Black. HBV genotype was A-14, B-12, C-14, other-8, unknown-90. During an average follow up of 6.5 years (range 1–23 years) after loss of HBeAg, 29 subjects cleared HBsAg. The cumulative rate of HBsAg loss was 41% among the treatment-related (86% inter-feron-related) and 9% among the spontaneous HBeAg loss cohort over average follow up of 6.5 years, 29% in those with genotype A and 3% in other genotypes. Factors associated with HBsAg loss were white race, genotype A, treatment-related HBeAg loss, higher initial ALT or AST, lower platelet count and higher APRI. Factors independently associated with HBsAg loss in stepwise logistic regression were shorter duration of HBeAg negativity, white race and higher baseline ALT. Conclusion: In long-term follow-up, patients with treatment-related HBeAg loss had higher rates of subsequent HBsAg loss compared to those with spontaneous HBeAg loss. Interferon-treated subjects who clear HBeAg continue to benefit many years after treatment is discontinued supporting continued use of interferon as a treatment option.

Disclosures:

The following people have nothing to disclose: Adil Abdalla, Anthony Loria, Xiongce Zhao, Joni Trenbeath, T. Jake Liang, Jay H. Hoofnagle, Marc G. Ghany

884

  1. Top of page

Single-Nucleotide Polymorphism PNPLA3 I148M is Associated With Steatosis and Steatohepatitis in Patients With Chronic Hepatitis B

Willem Pieter Brouwer1, Adriaan J. van der Meer1, Andre Boon-stra1, Zwier M. Groothuismink1, Annemiek A. van der Eijk1, Robert J. de Knegt1, Bettina E. Hansen1,2, Fiebo J. ten Kate3, Harry L. Janssen4,1;
1Gastroenterology & Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands; 2Public Health, Erasmus Medical Center, Rotterdam, Netherlands; 3Pathology, Erasmus Medical Center, Rotterdam, Netherlands; 4Gastroenterology & Hepatology, University Health Network, Toronto Western Hospital, Toronto, ON, Canada

Background & Aims. The I148M polymorphism of PNPLA3 is associated with hepatic fibrosis and steatosis in chronic hepatitis C. We aimed to assess the association between PNPLA3 and liver histology in chronic hepatitis B (CHB) patients. Methods. We analysed all consecutive treatmentnaïve CHB patients diagnosed from 1985 to 2012 for whom a liver biopsy was available for scoring by a single experienced pathologist and for whom a serum sample was available for genetic testing. Fibrosis (Ishak;0–6), steatosis (Brunt;>5%) and steatohepatitis (NASH; lipogranulomas and ballooning in the presence of steatosis) were determined. Overweight was defined as a bodymass index (BMI) >27.5kg/m2. Results. In total 578 patients were included; 386 (67%) were male, 291 (50%) HBeAg(+) and 47/31 /19/3% Caucasian/Asian/Black/other. Mean age at biopsy was 34.5 (SD 12.5) years. Viral genotype was A/B/C/D/E/unknown in 14/8/11/21/4/42%, respectively. Ninety-four (16%) patients were overweight. Cirrhosis was present in 64 (11 %), steatosis in 177 (31%), NASH in 100 (17%) and diabetes in 31 (5%) patients. PNPLA3 CC/GC/GG was present in 57/36/7%. PNPLA3 was associated with steatosis (OR=1.7, 95%CI:1.3–2.2;p<0.001) and NASH (OR=1.8, 95%CI:1.3–2.5;p=0.001), but not with fibrosis (b=-0.17, 95%CI:-0.38–0.05;p=0.130). In multivariate analysis adjusted for age, sex and BMI, PNPLA3 was associated with steatosis (OR=1.9, 95%CI:1.3–2.8;p=0.001), in contrast to race, alcohol intake and diabetes. Results for NASH were similar. The effect of PNPLA3 on NASH was less pronounced in overweight patients (OR 1.5, 95%CI:0.7–3.4;p=0.311), while stronger in those without overweight (OR 2.9, 95%CI:1.7–5.1;p<0.001). Conclusion. The I148M variant of PNPLA3 is associated with steatosis and NASH in CHB patients. The effect on NASH was most pronounced in patients without overweight.

Disclosures:

Adriaan J. van der Meer - Speaking and Teaching: MSD

Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

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

The following people have nothing to disclose: Willem Pieter Brouwer, Zwier M. Groothuismink, Annemiek A. van der Eijk, Bettina E. Hansen, Fiebo J. ten Kate

885

  1. Top of page

Duration of Virologic Response is a Significant Factor for Disease Progression and Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B during Oral Nucleos(t)ide Analogues Therapy

In Hee Kim, Jin Chang Moon, Seong Hun Kim, Sang Wook Kim, Seung Ok Lee, Soo Teik Lee, Dae Ghon Kim;
Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea

Background: Oral nucleos(t)ide analogues (NA) therapy have been successfully used for suppressing circulating serum viral loads. In this study, we investigated long-term effect of oral NA therapy on the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Methods: This retrospective study included 524 naïve CHB patients who had received oral NA therapy for more than 48 weeks between January 2003 and December 2012 at Chonbuk National University Hospital. Primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as any of cirrhosis development, cirrhotic complications, HCC, or liver-related mortality. Virologic response was defined as serum HBV DNA <20 IU/mL by real-time PCR. Results: Of total 524 patients, 340 (64.9%) were male, 360 (68.7%) were HBeAg positive, 188 (35.4%) had cirrhosis, and median follow up duration was 60 months (range 12–60). Cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4, 5 years were 0.2%, 1.2%, 2.3%, 7.1 %, 19.3% and 0.2%, 0.6%, 1.3%, 3.4%, 11.1%, respectively. In subgroup patients with cirrhosis at baseline, cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4, 5 years were 0.5%, 2.2%, 6.6%, 15.3%, 38.2%, and 0.5%, 1.6%, 3.5%, 8.0%, 26.2%, respectively. In the multivariate analysis, age>50 years (HR 1.97, 95% CI 1.13–3.44), cirrhosis (HR 3.15, 95% CI 1.57–6.33) were significant factors for disease progression and age>50 years (HR 2.42, 95% CI 1.00–5.88), family history of HCC (HR 5.32, 95% CI 2.08–13.62), cirrhosis (HR 19.39, 95% CI 5.15–73.04) were significant factors for HCC development. Furthermore, among on-treatment factors, duration of virologic response (>24 months) was significantly associated with disease progression (HR 0.14, 95% CI 0.06–0.32) and HCC development (HR 0.10, 95% CI 0.04–0.29). Conclusions: In addition to pretreatment factors such as age>50 years and cirrhosis, the duration of virologic response is a significantly associated with disease progression or HCC development in CHB patients under oral NA therapy.

Disclosures:

Soo Teik Lee - Management Position: chonbuk National University

The following people have nothing to disclose: In Hee Kim, Jin Chang Moon, Seong Hun Kim, Sang Wook Kim, Seung Ok Lee, Dae Ghon Kim

886

  1. Top of page

Poor recognition of risk factors for chronic hepatitis B virus infection among physicians who prescribe immunosuppressive therapy

Alissa Visram1, Jordana Boro2, Kelvin Chan3, Jordan J. Feld1, Lisa K. Hicks2;
1Toronto Western Hospital Liver Centre, University Health Network, University of Toronto, Toronto, ON, Canada; 2St. Michael's Hospital, University of Toronto, Toronto, ON, Canada; 3Odette Cancer Centre, Sunnybrook Hospital, University of Toronto, Toronto, ON, Canada

Background: Hepatitis B virus (HBV) reactivation is a potentially fatal outcome of immunosuppression. Fortunately, screening for HBV in patients at risk of chronic infection allows for the use of early antiviral prophylaxis to prevent reactivation. There is controversy about the optimal screening strategy. The Centers for Disease Control and Prevention (CDC) recommends screening all patients for HBV prior to immunosuppressive therapy (IST), while the American Society of Clinical Oncology recommends screening only patients at high risk for HBV. Aims: To determine whether physicians who prescribe IST are able to identify patients with risk factors for chronic HBV infection, as well as to assess screening rates and clinician awareness of screening guidelines. Methods: The study population consisted of physicians (hematologists, oncologists and rheumatologists) managing patients on IST. Patients completed a questionnaire that asked about their country of origin to determine if they were from an HBV-endemic region, the strongest risk factor for chronic HBV infection. Physicians were then given a follow up questionnaire to assess the risk status of the patient and outline their screening protocol. A chart review was conducted to compare the reported and actual screening practices of physicians. Results: Physicians were not able to reliably identify patients at high risk of chronic HBV infection due to their country of origin; only 2% of rheumatology patients, 15% of oncology patients, 53% of hematology patients from HBV-endemic areas were identified by physicians as high risk patients. Overall, hematologists were more likely to identify patients from endemic areas when compared to oncologists (p=0.009) and rheumatologists (p<0.001). The rate of screening prior to immunosuppressive therapy was unreliable; however, hematologists were more likely than both rheumatologists and oncologists to screen all patients prior to the start of IST, despite most physicians reporting familiarity with existing guidelines. For all groups, the reported rate of screening was lower than the actual rate documented by chart review. Conclusion: Physicians who prescribe immunosuppressive therapy are not reliably able to identify patients at high risk of HBV infection, and HBV screening rates are inconsistent. Guidelines recommending screening high-risk patients may be ineffective due to poor physician recognition of important risk factors. Recommendations to screen all patients may be a more effective strategy.

Disclosures:

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

The following people have nothing to disclose: Alissa Visram, Jordana Boro, Kelvin Chan, Lisa K. Hicks

887

  1. Top of page

Spontaneous loss of hepatitis B surface antigen in chronic carriers, based on a long-term follow-up study in Japan

Naota Taura1, Tatsuki Ichikawa1, Yuji Kato2, Kazuhiko Nakao1;
1Department of Gastroenterology and Hepatology, Nagasaki University School of Medicine, Nagasaki, Japan; 2Department of Gastroenterology and Hepatology, Oita Prefectural Hospital, Oita, Japan

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) serves as important serological markers for the diagnosis and monitoring of chronic hepatitis B patients (CHB). However, little is known about whether spontaneous HBsAg loss influences prognosis in patients with hepatitis B virus (HBV) infection. The aims of this study were to assess spontaneous seroclearance of HBsAg and difference in prognosis between patient with seroclearance of HBsAg and other in CHB. METHODS: Annual mass examination was performed between 1972 and 2004 in Tomie-town, Goto Islands, Japan, where HBV infection is very prevalent. The incidence of spontaneous loss of HBsAg in HBsAg carriers was determined in this area. Four thousand four hundreds eighty two inhabitants were tested for HBsAg and hepatitis B virus antibody (HBsAb) two or more times in our annual surveys. RESULTS: The results of survey were as follows: 227 (5%) patients were positive for HBsAg, 1,322 (30%) were positive for HBsAb and 2,933 (65%) were negative for HBsAg and HBsAb. A total of 1,085 deaths occurred in these subjects over a mean follow-up of 10.7 years: 57 deaths in the HBsAg-positive group, 408 in the HBsAb-positive group and 620 in both negative. The rates of death by liver disease in the HBsAg-positive group were 32%, whereas other groups were only 4% or 5%, liver-related deaths occurred more frequently among the HBsAg-positive group. Among them, 170 (3.7%) were defined as chronic HBsAg carriers based on the persistence of HBsAg for 1 or more years. These 170 subjects were followed for mean of 17.0 years. During the follow-up period, spontaneous loss of HBsAg occurred in 64 (38%) of the 170 carriers, with a yearly incidence of 1.8%. The patients were categorized into 2 groups as follows: (1) HBsAg loss group comprising patients with spontaneous loss of HBsAg and (2) HBsAg non-loss group comprising patients positive for HBsAg in period of surveillance. We analyzed and compared the 2 groups for the survival rates. The HBsAg loss group had a higher cumulative survival rate than the HBsAg non-loss group (P = <0.001). CONCLUSIONS: These results indicate that spontaneous loss of HBsAg was a yearly incidence of 1.8%. In addition, spontaneous loss of HBsAg is associated with lower rates of disease progression, and improved survival rates.

Disclosures:

The following people have nothing to disclose: Naota Taura, Tatsuki Ichikawa, Yuji Kato, Kazuhiko Nakao

888

  1. Top of page

Stopping antiviral therapy after successful rescue in chronic hepatitis B patients with decompensation is safe but demands off-therapy monitoring

Ming-Ling Chang, Rachel Wen-Juei Jeng, Yun -Fan Liaw;
Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taiwan

Background/Aims: Guidelines of major liver associations recommend that nucleot(s)ide analogue (NA) therapy should usually be continued indefinitely in chronic hepatitis B patients with decompensated cirrhosis. However, there is no evidence to support this recommendation. We therefore examined this issue using an earlier lamivduine treated cohort to study the outcomes of stopping NA therapy. Methods: The study patients included 280 patients with decompensated chronic hepatitis B (228 males; 115 cirrhosis) who were treated with lamivudine 100mg/day for 1–50 months and were followed-up after cessation of therapy for at least 12 months. Their baseline features are listed in Table. After stopping therapy, they were monitored every 1–3 in the first 6 months and then every 3–6 months. The incidence of off-therapy events including hepatic decompensation (DE), hepatocellular carcinoma (HCC) and mortality were compared between cirrhotic and non-cirrhotic patients using Kaplan-Meier estimates. Results: Events occurred in 24.64 % of the patients during a follow-up period of 12–180 (median:89.1) months after stopping therapy, including 55 DE (16%), 18 HCC (6.4 %) and 3 mortalities (1.1 %). The incidence of DE, HCC and mortality remained low in cirrhotic patients though significantly higher than that of non-cirrhotic counterparts (Table). Conclusion: The results of this retrospective study show that NA can be stopped safely in the majority of patients who were successfully rescued by NA therapy, even in cirrhotic patients. Proper off therapy monitoring is mandatory.

Table 1. 
CirrhosisAge (Yr|Male (%)ALT (U/L)Biliruhin (mg/dl)APTHBV DNA (107 IU/ml)Genotype B(%);C(%)DEHCCDeath
  1. DE: hepatic decompensation; ΔPT: prothrombin time prolonged, *: p<0.05

(N=115)46.0+/-11.4 I0I3.2+/-840.113.1 +/-I0.69.I+/-5.64.4+/-9.885%;I5%31 (27%)15(13%)3(2.69;)
neo (N=165)40.3+/-13.3127(77%)1551.6+/-1001.513.5+/-9.58.2+/-10.27.9+/-3.989%;11%24 (14.5%)3(1.8%)0(0%)
p values<0.001*0.078<0.001*0.7950.4620.480.3300.022*0.001*0.03*

Disclosures:

Yun -Fan Liaw - Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis; Grant/Research Support: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis

The following people have nothing to disclose: Ming-Ling Chang, Rachel Wen-Juei Jeng

889

  1. Top of page

Risk of Hepatocellular Carcinoma after HBsAg Seroclearance Associated with Nucleoside Analogue Therapy in Patients with Chronic Hepatitis B

Gi Ae Kim1, Seungbong Han2, Jihyun An1, Dong Jin Suh1, Young-Suk Lim1;
1Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Department of Biostatistics and Clinical Epidemiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background/Aim: Spontaneous or interferon-induced seroclearance of HBsAg is associated with a decreased risk of HCC. However, little is known about the long-term risk of hepatocellular carcinoma (HCC) after nucleoside/nucleotide analogue (NUC)-associated HBsAg seroclearance. Methods: Of 5374 consecutive patients with chronic HBV infection who commenced their first treatment with lamivudine (n=3374) or entecavir (0.5 mg/day, n=2000) between 1999 and 2011, a total of 120 achieved HBsAg seroclearance. Patients who had HCC before HBsAg seroclearance or follow-up period of less than 6 months after HBsAg seroclearance and treatment discontinuation were excluded. Incidence of HCC and transplant-free survival were compared between patients with and without HBsAg seroclearance by using propensity score matching adjustment to reduce selection bias. Results: Among a total of 83 patients with HBsAg seroclearance, only one who had cirrhosis at baseline developed HCC 6 months after HBsAg seroclearance. Another patient who had cirrhosis at baseline received liver transplantation 4 years after HBsAg seroclearance. Otherwise, none has progressed to hepatic decompensation. In the 73:292 (1:4) matched pairs of patients with and without HBsAg seroclearance, the incidence of HCC (hazard ratio [HR], 0.07; 95% confidence interval [CI], 0.01–0.55; p=0.01), the risk of death or liver transplantation (HR, 0.10; 95% CI, 0.01–0.76; p=0.03), and the composite outcome of death, liver transplantation, or HCC (HR, 0.11; 95% CI, 0.03–0.46; p<0.01) were significantly lower in HBsAg seroclearance group during the mean follow-up period of 10 years. Conclusion: HBsAg seroclearance achieved after NUC treatment was associated with minimal risk of HCC, death, or liver transplantation during long-term follow-up period.

Disclosures:

The following people have nothing to disclose: Gi Ae Kim, Seungbong Han, Jihyun An, Dong Jin Suh, Young-Suk Lim

890

  1. Top of page

Risk of sentinel events and benefits of surveillance for hepatocellular carcinoma - a prospective study with matched controls of 673 patients with chronic hepatitis B infection followed up over 10 years

Chee-Kiat Tan, Zhongxian Poh, Boon-Bee George Goh, Jason Chang;
Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore

Background: Development of cirrhosis(cirr) and hepatocellular carcinoma(HCC) are sentinel events in chronic liver disease. Hepatitis B is endemic in Singapore but there is no data on risk of cirr or HCC in patients(pts) with chronic hepatitis B infec-tion(CHBI). Although surveillance(surv) for HCC in CHBI pts is widely accepted as beneficial, long term prospective studies are lacking. Prospective studies matched against controls who did not receive surv provide robust evidence of benefit. Aims: To prospectively (1 )document risk of development of cirr and HCC in CHBI pts and (2)study benefits of surv for HCC compared against matched non-surv CHBI pts as controls. Methods: CHBI pts seen from 1 Sep 2003 to 31 Mar 2004 in Singapore General Hospital Dept of Gastroenterology and Hepatology outpt clinic were included in the study. Pt review was every 6mths with HCC surv (ultrasound/CT scan) every 6–12mths. Cirr was diagnosed by histology or imaging with supportive clinical evidence. HCC was diagnosed on dynamic CT/MRI scan. Census of follow-up and events was done 10 yrs later on 1 Mar 2013. Controls matched for age, gender and period of HCC diagnosis were obtained from 563 CHBI pts with HCC seen over the same period and who did not receive surv. Results: Study cohort comprised 673 pts with 62.6% males. Mean age was 56.4±12.7yrs. 545 pts(81%) were still on follow-up at 10 years. 86 developed cirr. Using Kaplan-Meier(KM) analysis, cirr risk was 2.1/8.7/12.9/17.8% at 1/5/8/10 yrs (∼1.8%/yr). There were 41 HCC cases and 1 /5/8/10-yr risk of HCC was 0.9/3.4/6.5/8.0% (∼0.8%/yr) overall and 8.1/13.9/23.1/29.8% (∼3%/yr) in cirr pts. Pts with HCC diagnosed during surv had significantly better Child-Pugh class, earlier HCC and better BCLC stage. More were also eligible for active HCC therapy (see Table, all p<0.01). KM survival analysis showed significantly better median survival in the surv group (107.1 vs 5.6mths, p<0.01). Summary: Cirr risk in CHB is ∼1.8%/yr and HCC risk ∼0.8%/yr. HCC risk increases 3.8-fold in cirr (∼3%/yr). Pts on HCC surv have improved survival that is not due to lead time bias as significantly more received active HCC therapy. Conclusion: Our 10-yr prospective matched control study shows that CHB pts on HCC surv have significantly earlier and treatable HCC and hence better median survival.

Significant differences between surveillance HCC cases and matched non-surveillance HCC controls

Table 2. 
 Surveillance (%)No surveillance (%)
  1. All p<0.01

Child-Pugh: A/B/C35/5/1 (85.4/12.2/2.4)22/14/5(53.7/34.1/12.2)
TNM: I-II/III-IV32/9 (78/22)18/23(43.9/56.1)
BCLC: 0/A/B/C/D13/21/6/1/0 (31.7/51.2/14.6/2.4/0)0/5/7/22/7 (0/12.2/17.1/53.7/17.1)
Surgery/ablation/no active therapy16/21/4(39/51.3/9.7)7/6/28(17.1/14.6/68.3)

Disclosures:

The following people have nothing to disclose: Chee-Kiat Tan, Zhongxian Poh, Boon-Bee George Goh, Jason Chang

891

  1. Top of page

Fatigue in Patients with Chronic Hepatitis B Not on Treatment from the U.S. and Canada: Preliminary Results from the Hepatitis B Research Network (HBRN)

Donna M. Evon1, Abdus S. Wahed2, Geoffrey Johnson2, Mandana Khalili3, Mauricio Lisker-Melman4, Jay H. Hoofnagle5;
1Medicine, University of North Carolina, Chapel Hill, NC; 2Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; 3Medi-cine, University of California, San Francisco, San Francisco, CA; 4Medicine, Washington University, St. Louis, MO; 5NIDDK Liver Disease Branch, NIH, Bethesda, MD

PURPOSE: Fatigue is the most common symptom of chronic liver disease, including chronic hepatitis B (CHB). Previous studies of fatigue in CHB relied on small sample sizes, single item or non-validated measures, and rarely assessed fatigue as a primary endpoint. The HBRN provides a unique opportunity to evaluate fatigue using a brief, standardized tool in a large observational multisite study. AIMS: 1) To assess whether fatigue is more common in patients with CHB compared to the general U.S. population, and 2) To identify sociodemographic and clinical features associated with fatigue. METHODS: Cross-sectional data from the HBRN cohort study involving 21 U.S. and Canadian sites were analyzed. Participants were English-speaking adults not on CHB therapy. Fatigue was measured using a standardized Fatigue 7-item scale developed by the NIH Patient Reported Outcomes Measurement Information System initiative. Higher scores indicate higher fatigue. The fatigue survey was completed by participants at week 48 or 72; clinical data were collected at the same visit. CHB fatigue raw scores were converted to T-scores and compared with U.S. population norms (mean of 50; standard deviation (SD) of 10). Bivariate associations between fatigue and potential sociodemographic and clinical features were explored using simple regression. Multiple linear regression was employed to identify independent correlates of fatigue significant at p<0.05. RESULTS: Data were available for 594 untreated patients: 51% female; mean age of 43; 72% Asian, 15% Caucasian; 12% African-American; 37% inactive carriers; 27% HBeAg negative; 80% with AST-Platelet

Ratio Index (APRI) less than 0.5. Fatigue was significantly less in patients with CHB (mean=46.7, SD=7.4) compared to U.S norms (p< .0001). In bivariate analyses, higher fatigue scores were significantly associated with Caucasian race, female sex, higher education, higher BMI, lower albumin, lower HBVDNA, higher APRI, more comorbidities (e.g., HCV and HDV), and taking lipid-lowering or diabetic agents. Fatigue was not associated with CHB phenotype (inactive vs. active), AST or ALT. In the multivariable analysis, lower serum albumin (β (regression coefficient)= −2.00, p=.031), Caucasian race (vs. Asian, β = 3.1, p<.001), more comorbidities (>= 3 vs. 0–2, β = 4.7, p < 0.01), unemployment (β = 2.6, p < 0.01), and post-baccalaureate education (vs. some grade school, β=3.0, p =0.001) were significantly associated with higher fatigue score. CONCLUSIONS: Untreated patients with CHB have less fatigue compared to U.S. general norms. Fatigue in CHB is associated more so with sociodemographic factors than with markers of liver disease.

Disclosures:

Donna M. Evon - Grant/Research Support: Gilead

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

Mauricio Lisker-Melman - Speaking and Teaching: Gilead, GlaxoSmithKline, Inter-mune, Roche, Valeant, Schering-Plough, Novartis, Gilead, GlaxoSmithKline, Inter-mune, Roche, Valeant, Schering-Plough, Novartis, Gilead, GlaxoSmithKline, Intermune, Roche, Valeant, Schering-Plough, Novartis, Gilead, GlaxoSmithKline, Intermune, Roche, Valeant, Schering-Plough, Novartis

The following people have nothing to disclose: Abdus S. Wahed, Geoffrey Johnson, Jay H. Hoofnagle

892

  1. Top of page

Effect of sustained viral remission on long-term outcome of patients with hepatitis B virus-related cirrhosis presenting with decompensated complications: a prospective cohort study

Jeong Won Jang1, Young Seok Kim2, Hyun Young Woo3, Sung Kyu Choi4, Chang Hyeong Lee5, Tae Yeob Kim6, Won Young Tak7, Jong Young Choi1;
1Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Soonchunhyang University, Bucheon, Republic of Korea; 3Pusan National University, Busan, Republic of Korea; 4Chonnam National University, Gwangju, Republic of Korea; 5Catholic University of Daegu, Daegu, Republic of Korea; 6Hanyang University, Guri, Republic of Korea; 7Kyungpook National University, Daegu, Republic of Korea

Background: The effect of viral suppression on long-term survival of patients with hepatitis B virus (HBV)-related decompensated cirrhosis has not been established. The aim of the study was to evaluate the outcome in relation to viral suppression in these patients over 7 years. Methods: This was a prospective, multicenter, inception cohort study of subjects with HBV-related liver cirrhosis presenting with the first onset of decompensated complications. The primary end point was survival free of liver transplantation. Patients were followed up until death or transplantation. Data were analyzed on an intention-to-treat basis. Results: A total of 707 patients were enrolled in this study; 423 received antiviral therapy. Significant improvement in liver biochemical tests was observed in a subset of patients in the treatment group who remained in the study at 1 year. Despite higher HBV DNA levels and Child-Pugh scores at baseline in the antiviral-treatment group, the overall transplant-free survival was significantly better in the early antiviral-treatment group than untreated group (7 year-survival rates of 52.0% vs. 37.4%, respectively), with more apparent significance with advancement of Child-Pugh class and high-viremia group. In the treated group, the survival was significantly better in patients with than in those without virological remission. During the follow-up, transplant-free survival was independently associated with response to treatment, being significantly better in sustained responders than in non-sustained responders or untreated cases (7-year survival: 63.3%, 43.3% vs. 36.9%, respectively). With multivariate analysis, antiviral treatment and sustained viral response as well as hepatic functional parameters remained independently predictive of survival. Conclusions: Sustained viral remission under antiviral therapy in patients with cirrhosis complications leads to improved long-term survival, compared with non-sustained responders or untreated patients. In these particular patients, potent antiviral drugs with low resistance rate should be promptly administered under consideration for liver transplantation.

Disclosures:

Won Young Tak - Advisory Committees or Review Panels: Gilead Korea; Grant/Research Support: SAMIL Pharma; Speaking and Teaching: BMS Korea

The following people have nothing to disclose: Jeong Won Jang, Young Seok Kim, Hyun Young Woo, Sung Kyu Choi, Chang Hyeong Lee, Tae Yeob Kim, Jong Young Choi

893

  1. Top of page

The independent effects of chronic hepatitis B and teno-fovir on kidney function decline among HIV-infected men: a cohort analysis

Christopher J. Hoffmann1, Eric C. Seaberg2, Robert Bolan3, Lawrence Kingsley4, Frank Palella5, Chloe L. Thio1;
1Johns Hopkins University School of Medicine, Baltimore, MD; 2Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD; 3LA Gay & Lesbian Center, Los Angeles, CA; 4Infectious Diseases & Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; 5Medicine, Northwestern University School of Medicine, Chicago, IL

Background: Among HIV-infected individuals, both chronic hepatitis B (CHB) and tenofovir (TDF) use are reported risks for declines in kidney function. TDF also is an important treatment for HIV-CHB co-infected patients. We explored whether the effects of CHB and TDF on kidney function were independent or synergistic, using a cohort of prospectively-followed men in the US. Methods: Subjects were HIV-infected men from the Multi-center AIDS Cohort Study who had received TDF after it was approved in 2001 and were serologically negative for HCV infection. We included data from all visits 2 years prior to and 5 years after TDF start. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula. Mixed-effects linear regression was used to estimate eGFR decline and the individual contribution of TDF and of CHB on the annual change in eGFR by modeling an interaction term between time and each of TDF and CHB. We also assessed whether the effects of TDF and CHB on declines in kidney function were independent by modeling an additional interaction term. Multi-variable models controlled for age, baseline eGFR, time-updated CD4 count, and history of antiretroviral therapy (ART) prior to TDF. Results: 324 men (17 with HIV-CHB co-infection) contributed a mean of 11.2 eGFR measures (11 for those without CHB and 8 for those with CHB). The median age was 34 (IQR: 30, 39) and median CD4 count at TDF initiation was 426 cells/uL (IQR: 296, 651); 288 (89%) were switched to TDF from other ART agents. Men with HBV had more rapid declines in eGFR both before and during TDF use. In addition, eGFR decline increased during TDF use; however, there was no evidence of an interaction between CHB and TDF - the contributions of each to eGFR decline appeared to be independent (p for interaction >0.1). In the final model, men without CHB had an annual eGFR change pre-TDF of −1.2 ml/min (95% CI: −2.0, −0.25) compared to −2.8 ml/min (95% CI: −3.9, −1.6) for men withCHB (P<0.001). On-TDF, the eGFR change was −1.8 (95% CI: −2.2, −1.4) for men without CHB compared to −3.4 (95% CI: −4.2, −2.6) for men with CHB (P<0.001). Regardless of CHB presence, eGFR declines were significantly greater on-TDF compared to pre-TDF (p<0.001); although CHB did not exacerbate eGFR declines during TDF use (P>0.1). Conclusions: Among HIV-infected men, CHB co-infection is associated with more rapid declines in kidney function compared to men without CHB. CHB's acceleration of eGFR decline persists during TDF use despite TDF's potent anti-HBV activity. Monitoring renal function is especially important among HIV-CHB co-infected patients.

Disclosures:

The following people have nothing to disclose: Christopher J. Hoffmann, Eric C. Seaberg, Robert Bolan, Lawrence Kingsley, Frank Palella, Chloe L. Thio

894

  1. Top of page

Development and Validation of An HBV-load-free Hepatocellular Carcinoma Risk Calculator

Hwai-I Yang1,2, Tai-Chung Tseng3,9, Henry Lik-Yuen Chan4, Mei-Hsuan Lee5, Jessica Liu2, Richard Batrla-Utermann7, Uchenna Iloeje8, Jia-Horng Kao9, Chien-Jen Chen2,6;
1Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 2Genomics Research Center, Academia Sinica, Taipei, Taiwan; 3Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan; 4Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong; 5Grad-uate Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 6Graduate Institute of Epidemiology and Preventive Medicine, School of Public Health, National Taiwan University, Taipei, Taiwan; 7Roche Diagnostics, Ltd., Basel, Switzerland; 8Bris-tol-Myers Squibb Co., Wallingford, CT; 9Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan

Background and aim As the hepatitis B virus (HBV) DNA test is relatively expensive and recent evidences suggest that quantitative hepatitis B surface antigen (HBsAg) level provides additional predictability on hepatocellular carcinoma (HCC) especially in patients with hepatitis B e antigen (HBeAg)-seronegative and low HBV DNA. This study aimed to develop a risk score, replacing HBV DNA level with quantitative HBsAg level, and validate them externally using clinical patients in Hong Kong and Taiwan. Methods The community-based REVEAL-HBV cohort was used as the derivation set (n=3,584; 208 HCC cases). Two risk scores in which one integrated serum HBsAg level and the other further excluded HBV DNA level, was developed to predict 3-, 5-, and 10-yr HCC risk using a multivariate Cox proportional hazards model; and was externally validated in clinical patients from Chinese University of Hong Kong and the ERADICATE-B cohort from National Taiwan University Hospital (n=3,114; 237 HCC cases). The discriminatory accuracy was evaluated by calculating the area under receiver operating curve (AUROC); and the calibration by determining the extent of agreement between predicted and observed HCC risk using calibration chart and the Hosmer-Lemeshow goodness-of-fit test. Results The simplified model included sex, age, serum alanine aminotransferase level, and a combined variable of HBeAg status and quantitative HBsAg level as risk parameters. The potential risk score of this viral-load-free model ranged 0–15, which predicted the HCC risk with range of 0.01 %-13.4%, 0.02%-27.4%, and 0.1%-73.1%, at 3-year, 5-year, and 10-year, respectively. Applying score (model) to predict 3-, 5-, and 10-year HCC risk in the validation cohort, AUROCs were 0.904 (0.931), 0.807 (0.825), and 0.794 (0.807), respectively. All risk scores (models)-predicted HCC risk were well calibrated with the Kaplan-Meier-observed HCC risk. The P value of the Hosmer-Lemeshow goodness-of-fit test = 0.93 (0.91), 0.81 (0.44), and 0.69 (0.51), respectively, for score (model)-predicted 3-, 5-, and 10-year risk. AUROCs were quite similar using the HBV-load-free and HBV-load-con-taining HCC risk prediction models/scores. Conclusion It may be more cost-effective to replace serum HBV DNA level by serum HBsAg level for the simplified version of HCC risk calculator, which can be applicable as a first-line instrument for large-scale community surveys and in regions where medical resources are limited.

Disclosures:

Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Vertex, Bristol-Myers Squibb, Abbott, Novartis Pharmaceutical, Roche, MSD

Richard Batrla-Utermann - Employment: Roche, Roche, Roche, Roche

Uchenna Iloeje - Employment: Bristol-Myers Squibb, Bristol-Myers Squibb, Bristol-Myers Squibb, Bristol-Myers Squibb

The following people have nothing to disclose: Hwai-I Yang, Tai-Chung Tseng, Mei-Hsuan Lee, Jessica Liu, Jia-Horng Kao, Chien-Jen Chen

895

  1. Top of page

Increase in inducible interferon-γ protein 10 (IP 10) during long-term therapy with nucleos(t)ide analogues in chronic hepatitis B predicts efficient viral suppression

Matthew J. Bruce, Mary Horner, Deepak Joshi, Sarah A. Hughes, Kate Childs, Phillip M. Harrison, Kosh Agarwal, Ivana Carey;
Institute of Liver Studies, Kings College School of Medicine at King's College Hospital, London, United Kingdom

Long-term often life-long therapy with nucleos(t)ide analogues (NA) is required to control HBV DNA suppression in chronic hepatitis B (CHB). Only few studies demonstrated maintaining long-term viral response in 55% patients after cessation of NA therapy. Changes in inducible interferon-γ protein 10kDa (IP10) plasma levels predicted HBsAg loss in patients with long-term viral response. Detailed virological, serologic and immunolog-ical characteristics including HBV DNA, plasma HBsAg and IP10 levels at NA therapy baseline and its changes during long-term NA therapy to identify potential candidates for therapy cessation were investigated by this study. Patients: 101 chronic hepatitis B (CHB) monoinfected patients (median age 43 years, 69 males, 25% HBeAg+) with mild/moderate disease (Ishak F2/F3 fibrosis) were treated with entecavir (ETV) 0.5mg/day (n=50) or tenofovir (TDF) 245mg/day (n=51) for at least 4 years. All achieved virological response (VR= HBV DNA<20 IU/ml) after year 1 therapy and based on qualitative response at year 2 evaluated by COBAS AmpliPrep COBAS Taqman HBV test (CAP-CTM; Roche Molecular Systems Inc.) were divided into 2 groups: HBV DNA <20 IU/ml not detected (ND) (n=55) and HBV DNA <20 IU/ml detected (D) (n=46). Methods: HBsAg plasma levels were measured by Abbott ARCHITECT® assay, HBV DNA by real-time PCR [both log 10 IU/ml] and IP10 levels by ELISA [pg/ml] at baseline, year (Y) 1, 2, 3, 4 and 5 of therapy. Results are presented as medians. Results: Baseline, year 1 and 2 HBV DNA, HBsAg and IP10 levels were similar in ND and D patients and on ETV or TDF therapy. At year 3 IP10 levels were higher in ND than D patients (145 vs. 99, p=0.03), increased in ND when compared to baseline (104 vs. 109, p=0.3) and remain high at year 4 and 5 (Y4: 138 vs. 103, p=0.03;Y5: 146 vs. 102, p=0.01). HBsAg and ALT were similar in ND and D patients in all time-points. There were no differences in HBV DNA, HBsAg and IP10 between ETV and TDF during therapy. 50% patients had HBeAg sero-conversion between year 1–2 and it was similar in ND and D patients and on ETV or TDF therapy and was not associated with IP 10 changes. HBsAg loss occurred in 7% patients all in ND group after 4 years of therapy, was associated with increase in IP10 levels above 150 pg/ml. Conclusions: Increase in IP10 levels (>150 pg/ml) after 3 years of HBV DNA suppression with nucleos(t)ide analogues in chronic hepatitis B patients predicted undetectable HBV DNA (PPV 87%), was associated with HBsAg loss and might assist to identify potential candidates for nucleos(t)ide analogues therapy cessation.

Disclosures:

Kosh Agarwal -Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

The following people have nothing to disclose: Matthew J. Bruce, Mary Horner, Deepak Joshi, Sarah A. Hughes, Kate Childs, Phillip M. Harrison

896

  1. Top of page

Hepatitis B Surface Antigen Level is associated with Viral Reactivation in Spontaneous HBeAg Seroconvert-ers with Low Viral loads

Tai-Chung Tseng1, Chun-Jen Liu2, Tung-Hung Su2, Hung-Chih Yang2, Pei-Jer Chen2, Ding-Shinn Chen2, Jia-Horng Kao2;
1Internal Medicine, Buddhist Tzu Chi General Hospital Taipei Branch, Taipei, Taiwan; 2Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Background & Aims: Level of hepatitis B surface antigen (HBsAg) has been shown to complement HBV DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg sero-converters remains unclear. Methods: A cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV DNA/ HBsAg levels and HBeAg-negative hepatitis/ active viral replication (HBV DNA level ≧2000 IU/mL) were investigated. Results: In the overall cohort, serum HBV DNA level served as a better predictor for HBeAg-negative hepatitis compared to HBsAg level. However, in those with HBV DNA level <2000 IU/mL, a higher HBsAg level was associated with higher risk of HBeAg-negative hepatitis (P=.015, Figure 1). Multivariate analysis showed the hazard ratio of HBsAg level ≧ 1000 IU/mL versus <1000 IU/mL was 4.1 (95% confidence interval: 1.3–13.6). When using the endpoint of active viral replication, HBsAg ≧ 1000 IU/mL remained as an independent risk factor. Conclusions: Our data show the higher HBsAg level is associated with increased risks of HBeAg-negative hepatitis and active viral replication in spontaneous HBeAg seroconverters with low viral loads.

Disclosures:

Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK, Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche

Ding-Shinn Chen - Consulting: BMS, GSK, Gilead, Roche, Merck, BMS, GSK, Gilead, Roche, Merck

The following people have nothing to disclose: Tai-Chung Tseng, Chun-Jen Liu, Tung-Hung Su, Hung-Chih Yang, Jia-Horng Kao

897

  1. Top of page

IL-28B Genotypes in Spontaneous and Treatment Induced HBsAg Clearance of Chronic Hepatitis B Patients

Emilia Hadziyannis1, Andreas Laras2, Elieni Panopoulou2, Sofia Anagnostopoulou2, Stephanos J. Hadziyannis2;
12nd Dpt of Internal Medicine, National and Kapodistrian University of Athens Medical School, Hippokration Hospital, Athens, Greece; 2Molecular Biology Laboratory of the Liver Unit at the Evgenidion Hospital, National and Kapodistrian University of Athens, Athens, Greece

IL-28B polymorphism has been documented to influence the response to IFN-α plus ribavirin therapy in chronic hepatitis C. Data on chronic hepatitis B (CHB) are limited and findings are contradictory. Aim: To investigate whether sustained virological responses and HBsAg loss in IFN and nucleos(t)ide analogue (NA) treated patients with HBeAg-negative chronic HBV infection are linked with IL-28B genotypes rs12979860 and the prevalence of the favorable C allele. Methods: A total of 606 Greek subjects were included, 366 with HBeAg negative chronic HBV-genotype D infection and 240 healthy Caucasians of Hellenic ethnicity. The HBV infected patients belonged to subgroups: 1. CHB treated with IFN-α for at least one year 2.CHB treated with NAs without development of resistance. 3.HBsAg carriers with and without spontaneous HBsAg loss 4.CHB who developed hepatocellular carcinoma (HCC). Blood or sera stored at −70 C were assessed for the rs12979860 genotypes and the prevalence of C/T alleles in the IL-28B locus with the LightMix IL28B, LightCycler, Roche. Results: The prevalence of the IL-28B genotypes and C and T alleles among healthy Greek individuals and in various groups of CHB patients is depicted in the table. The response rate to IFN among patients with genotype CC, CT and TT was not different. Similarly no difference in IL-28B genotypes was observed among patients who achieved sustained response and HBsAg loss during and after stopping NA therapy. Spontaneous loss of HBsAg in inactive carriers was not associated with the favorable C allele of IL-28B. In patients with HBV induced HCC there was no clustering of any IL-28B genotype. Conclusions: The results of IL-28B polymorphism in the tested Caucasian population infected with HBV genotype D, in contrast to recent findings from Italy, indicate that: 1 .In HBeAg-negative CHB patients treated either with IFN or NAs a favorable long term outcome terminating in HBsAg loss is not associated with the IL-28B genotype CC rs12979860 or with the prevalence of C allele. 2.Spontaneous HBsAg loss among inactive carriers is not linked with any IL-28B genotype or with the prevalence of C allele 3.In patients with HBV related HCC the distribution of IL-28B genotypes and C-T alleles do not differ from CHB without HCC.

Prevalence of IL-28B genotypes and C - T alleles of rs 12979860

Table 3. 
IL-28B Genotype %Healthy IndividualsCHB responders to IFNCHB responders to NAsInactive Carriers with HBsAg lossHCC
CC3512364443
CT5364444438
TT1224201219
Allele %     
C6244586662
T3856423438

Disclosures:

Stephanos J. Hadziyannis - Advisory Committees or Review Panels: Gilead, Bristol-Myers Squibb, Novartis, Pfizer, Gilead, Bristol-Myers Squibb, Novartis, Pfizer, Gilead, Bristol-Myers Squibb, Novartis, Pfizer, Gilead, Bristol-Myers Squibb, Novartis, Pfizer; Grant/Research Support: Roche, Gilead, Shering Plolugh, Roche, Gilead, Shering Plolugh, Roche, Gilead, Shering Plolugh, Roche, Gilead, Shering Plolugh, Janssen; Speaking and Teaching: Roche, Roche, Roche, Roche

The following people have nothing to disclose: Emilia Hadziyannis, Andreas Laras, Elieni Panopoulou, Sofia Anagnostopoulou

898

  1. Top of page

Spontaneous hepatitis B e-antigen seroconversion without subsequent antiviral therapy is associated with higher rates of hepatitis B surface antigen seroclearance

James Fung, Danny Wong, Wai-Kay Seto, Ching-Lung Lai, Man-Fung Yuen;
Medicine, University of Hong Kong, Hong Kong, China

Background: In chronic hepatitis B (CHB), the implications of hepatitis B e-antigen (HBeAg) seroconversion on subsequent hepatitis B surface antigen (HBsAg) seroclearance has not been documented. Methods: The Chronic Hepatitis B E-Seroconver-sion Study (C.H.E.S.S.) cohort follows up a large population of CHB patients with documented HBeAg seroclearance. Patients are followed-up at 3–6 monthly intervals with routine liver biochemistry and viral serological tests. Results: A total of 803 patients with documented HBeAg seroconversion were included, with a median HBeAg seroconversion age of 34 years. The median follow-up length was 123 months after HBeAg seroclearance, with a total of 9250 patient-years. Of these, 502 (62.5%) were male. The cumulative rate of HBsAg seroclearance after HBeAg seroconversion was 0.2%, 1.4%, 3%, and 15% after 1,5, 10, and 20 years respectively, without any gender differences (p=0.756). The median time to HBsAg seroclearance after HBeAg seroconversion was 139 months. 448 (55.8%) remained treatment-naïve after spontaneous HBeAg seroconversion (group 1), 204 (25.4%) had treatment-induced HBeAg seroconversion (group 2), and 151 (18.8%) required antiviral treatment after spontaneous HBeAg seroconversion. The HBsAg seroclearance rate observed in groups 1, 2, and 3 at 10 years were 4.3%, 2.6%, and 0% respectively, and at 20 years were 24%, 7.2%, and 0% respectively (p<0.001) (see figure). No HBsAg seroclearance was observed for group 3. The age of spontaneous HBeAg seroconversion was lower in group 1 compared with group 3 (32 vs 39 years respectively, p<0.001). Conclusion: In CHB, early spontaneous HBeAg seroconversion is associated with lesser chance of active HBeAg-negative disease and higher chance of HBsAg seroclearance. HBsAg seroclearance is rare for those who spontaneously undergo HBeAg seroconversion with subsequent reactivation requiring antiviral therapy.

Disclosures:

James Fung - Speaking and Teaching: Bristol Myers Squibb

Wai-Kay Seto - Advisory Committees or Review Panels: Gilead Science; Speaking and Teaching: Gilead Science

Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc; Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc

Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science

The following people have nothing to disclose: Danny Wong

899

  1. Top of page

HBV-Associated Hepatocellular Carcinoma (HCC): Gene Expression Profiling of Microdissected Hepatocytes Versus Whole Liver Tissue

Marta Melis1, Giacomo Diaz2, David E. Kleiner3, Jinping Lai3, Fausto Zamboni4, Giulia Mogavero4, Ashley B. Tice1, Jeffrey Hanson5, Jaime Rodriguez-Canales5, Michael R. Emmert-Buck5, Patrizia Farci1;
1Hepatic Pathogenesis Section,Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD; 2Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; 3Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, MD; 4Liver Transplantation Center, Hospital Brotzu, Cagliari, Italy; 5Pathogenetics Unit, Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, MD

Laser capture microdissection (LCM) permits the isolation of relatively pure cell populations for transcription analysis, adding a powerful tool to investigate the pathogenesis of HCC. This study describes the first known comparison of gene expression profiling obtained from whole liver tissue (WLT) and LCM from 11 livers with HBV-associated HCC from patients undergoing liver transplantation or resection. Biopsies, one from the center of the tumor and one from the most distant non-tumorous tissue, were analyzed using Affymetrix HU133 Plus2.0. WLT samples were analyzed as tumor vs. non-tumor and LCM samples as malignant vs. non-malignant hepatocytes. Microarray data showed 996 genes differentially expressed in WLT, 28% of which were upregulated in the tumor. Genes differentially expressed in LCM were 1,204, 49% of which were upregulated in malignant hepatocytes. The discrepancies between WLT and LCM data are indicative of the different cell composition of the samples. However, a common set of 736 genes was identified both in WLT and LCM. In addition, functional analysis showed 9 pathways common to WLT and LCM among the 15 top-scored canonical pathways identified by Ingenuity Pathway Analysis. Common pathways were mostly downregulated and included a remarkable predominance of drug (bupropion degradation, estrogen, and acetone degradation) and lipid (LPS/IL1 mediated inhibition of RXR function, PXR/RXR activation, and nicotine degradation II, and III) metabolism-related pathways. Next, we separately analyzed the genes common to the two techniques (736 genes) and those unique to WLT and LCM (260 and 468 genes, respectively). Common genes confirmed the prevalence of downregulated pathways with an enrichment of metabolism-related ones. On the other hand, a different set of pathways resulted from the analysis of unique genes. Specifically, LCM showed a predominance of upregulated pathways including cell remodeling (integrin and adherens junction) and cell motility (Rac and RhoA). But the most interesting finding was the identification of cancer/testis antigens (CTAs) genes, typically restricted to the testis in normal adults, overexpressed in malignant hepatocytes, including NUF2, which was not previously associated with HCC. Conclusion: HBV HCC samples were characterized by a majority of downregulated, predominantly metabolism-associated, genes. The LCM technique identified a number of unique genes, including a promising category of genes, CTAs, that were among the most upregulated genes in malignant hepatocytes. These findings may add new insights for understanding the pathogenesis of liver cancer and for devising new diagnostic and therapeutic strategies.

Disclosures:

Michael R. Emmert-Buck- Patent Held/Filed: Arcturus Engineering, Life Technologies

The following people have nothing to disclose: Marta Melis, Giacomo Diaz, David E. Kleiner, Jinping Lai, Fausto Zamboni, Giulia Mogavero, Ashley B. Tice, Jeffrey Hanson, Jaime Rodriguez-Canales, Patrizia Farci

900

  1. Top of page

Differences in Epidemiological and Clinical Characteristics in US- versus foreign-born Americans of African Descent with Chronic Hepatitis B Enrolled in the HBRN Cohort

Mohamed A. Hassan2, Coleman Smith2, Ruosha Li6, Michael W. Fried3, Richard K. Sterling4, Marc G. Ghany5, Abdus S. Wahed6, W. Ray Kim1;
1Mayo Clinic College of Medicine, Rochester, MN; 2University of Minnesota, Minneapolis, MN; 3University of North Carolina, Chapel Hill, NC; 4Medical College of Virginia, Richmond, VA; 5National Institutes of Health, Bethesda, MD; 6University of Pittsburgh, Pittsburgh, PA

Background/Aims: The majority of Americans with chronic hepatitis B virus (HBV) infection are foreign born. While the prevalence of HBV infection is higher in Americans of African descent than white Americans, detailed data about these 2 groups are scarce. We compare the demographic, epidemiological and clinical characteristics between US-born (USAA) and foreign-born African Americans (FBAA). Methods: Subjects of African descent enrolled in the NIH-funded Hepatitis B Research Network (HBRN) cohort study were identified by self-reported race. Serum HBV DNA and genotype were determined by central laboratories, supplemented by local data. Demographic and disease characteristics were compared between USAA and FBAA. Results: Of 1586 adult participants with chronic HBV infection, 220 were of African descent, including 56 USAA and 163 FBAA (74%). FBAA included 55 from West Africa, 95 from East Africa and 13 from other parts of the world. USAA were older, more likely to have history of sexually transmitted disease (43% versus 9%) or same-gender sex (9% versus 1 %) than FBAA (all p<0.05). USAA were more likely to be HBeAg-positive, have higher HBV DNA levels and be characterized by their physician to have HBeAg-positive chronic hepatitis, whereas FBAA were more likely to be inactive carriers. Although genotype A was most common in both groups (81% versus 50%), a substantial proportion of FBAA had genotype E (30%) or D (12%), neither of which was found in USAA. In the comparison between FBAA from West and East Africa, the former were more likely to have abnormal ALT (82% versus 46%, p<0.01) and higher HBV DNA level (3.4 versus 2.7 log10 IU/mL, p<0.01). The predominant genotype among West African FBAA was E (60%), whereas genotypes A (67%) and D (23%) were common in East African FBAA. Conclusion: Significant clinical and virological differences were found between USAA and FBAA, which may be attributable to differences in HBV epidemiology as well as genotype. USAA and West African FBAA appear to have a profile (high ALT and HBV DNA) associated with more active liver disease at enrollment. Longitudinal follow-up is ongoing to determine long-term outcomes.

Table 4. 
(GroupUSAA (n=56)FBAA (n=163)
  1. * p<0.05

MedianAge* (years)4740
 Men46%58%
Sexual Transmission*58%4%
HBeAg-positive*19%5%
Median ALTMale (U/L)*5835
 Female (U/L)2120
HBV DNA*<103 IU/mL38%48%
 103-107 IU/mL47%48%
 >107 IU/mL15%3%

Disclosures:

Mohamed A. Hassan - Speaking and Teaching: 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

Michael W. Fried - Advisory Committees or Review Panels: GlaxoSmithKline; Consulting: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead, Novartis; Grant/Research Support: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead

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

The following people have nothing to disclose: Ruosha Li, Marc G. Ghany, Abdus S. Wahed

901

  1. Top of page

Efficacy and safety of long term entecavir in Chronic Hepatitis B NUC naïve patients in real life

Ezequiel Ridruejo1,2, Sebastian Marciano3, Omar A. Galdame3, María Virginia Reggiardo4, Alberto Muñoz5, Raúl Adrover6, Daniel R. Cocozzella6, Nora C. Fernández7, Claudio R. Estepo8, Manuel Mendizabal2, Gustavo Romero5, Diana Levi5, Teresa Schroder8, Silvia Paz8, Hugo Fainboim8, Oscar G. Mandó1, Adrian Gadano3, Marcelo O. Silva2;
1Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno" CEMIC, Buenos Aires, Argentina; 2Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina; 3Hospital Italiano, Buenos Aires, Argentina; 4Hospital Provincial del Centenario/Sanatorio Americano, Rosario, Argentina; 5Hospital Bomorino Udaondo, Buenos Aires, Argentina; 6Centro de Hepatologia, La Plata, Argentina; 7Hospital Britanico, Buenos Aires, Argentina; 8Hospital Francisco J Muñiz, Buenos Aires, Argentina

Background: Registration studies showed Entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been well established. Aim: Evaluate long term efficacy and safety of ETV in real life. Methods: We evaluated HBV DNA clearance, HBeAg/antiHBe seroconversion and HBsAg/anti-HBs seroconversion rates in HBeAg-positive and negative NUC naïve HBV patients treated with ETV for more than 6 months. We evaluated baseline and on treatment predictor factors of serologic and virologic response. Adverse events were recorded. Treatment indication, duration and monitoring were defined according to national and international guidelines. Results: A hundred and sixty nine consecutive patients were treated with ETV for 183 ±81 weeks. 61% were HBeAg positive, 23% were cirrhotics (11 patients with decompensated cirrhosis before ETV), mean HBV-DNA levels were 6,88 ±1,74 log10 IU/ml, and mean ALT levels were 139 ±231 IU/ml. Overall, 156 (92%) patients became HBV DNA undetectable (Figure). In HBeAg positive patients, 92 (88%) became HBV DNA undetectable; with 83%, 85%, 89% and 100% on-treat-ment response rates at 96, 144, 192 and 240 weeks, respectively. In HBeAg negative patients, 64 (98%) became HBV DNA undetectable; with 91%, 95%, and 100% on-treatment response rates at 96, 144, and 192 weeks, respectively. HBeAg negative status (OR 8.8, 95CI% 1.11–69.36, p 0.039) and duration on ETV treatment (OR 1.01, 95CI% 1.005–1.02, p 0.003) were associated with higher undetectable HBV DNA rates. Seventy four (71%) patients became HBeAg negative and 71 (68%) antiHBe positive, after 70 ±42 weeks of treatment; 23 (14%) patients became HBsAg negative and 22 (13%) antiHBs positive, after 96 ±46 weeks of treatment (Figure) .Twenty three (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) and 22 (13%) patients developed anti-HBs (Figure). At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive (16 antiHBs positive) and 2 HBeAg negative; 9 of them (26%) developed virological relapse after 51 ±34 weeks. None of the patients had primary non response. One patient developed breakthrough associated to resistant variants (189M, 202G y 204V). Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported. Conclusion: Long term ETV treatment showed high virological response rates and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in real life.

Disclosures:

Hugo Fainboim - Speaking and Teaching: Bristol Myers Squibb

Marcelo O. Silva -Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott; Board Membership: BMS; Grant/Research Support: Schering Plough, BMS; Speaking and Teaching: Schering Plough, BMS, MSD

The following people have nothing to disclose: Ezequiel Ridruejo, Sebastian Marciano, Omar A. Galdame, María Virginia Reggiardo, Alberto Muñoz, Raúl Adrover, Daniel R. Cocozzella, Nora C. Fernández, Claudio R. Estepo, Manuel Mendizabal, Gustavo Romero, Diana Levi, Teresa Schroder, Silvia Paz, Oscar G. Mandó, Adrian Gadano

902

  1. Top of page

Poor Adherence to AASLD Guidelines for Chronic Hepatitis B Management in a Large Academic Medical Center

Ying Wu1, Kara B. Johnson1,2, Joanna Lopez3, Hui Zheng1, Giorgio Roccaro3, Anthony Muiru3, Nneka Ufere3, Omar Kattan3, Raymond T. Chung1;
1Gastroenterology, Massachusetts General Hospital, Boston, MA; 2Harvard Medical School, Boston, MA; 3Internal Medicine, Massachusetts General Hospital, Boston, MA

BACKGROUND: Over one million Americans have chronic hepatitis B (CHB). Close monitoring of patients is essential because of spontaneous transitions between stages of infection that may require treatment. This study evaluates adherence to AASLD guidelines for each phase of infection in a large cohort of CHB patients. METHODS: Retrospective cohort study of 985 CHB patients followed between 2005 - 2012. Statistical analyses used the chi-square test and logistic regression. RESULTS: Median age was 45 [37, 56] years, 78% were non-white, 22% did not list English as their primary language. Infection phases: 389 (40%) inactive carriers; 262 (26%): e-antigen negative hepatitis; 142 (14%): immune active; 11 (1%): immune tolerant. Care provided by gastroenterology (GI) in 62%; primary care (PCP) in 23%; co-managed by both in 6%. 1) Treatment Adherence: 526 patients (54%) were treatment eligible, but 115 (22%) did not receive treatment. Of this group, 74% (85) had eAg(-) hepatitis. In contrast, less than 2% of immune active (eAg+) patients were untreated. In the multivariate model, the odds of GIs adhering to treatment guidelines were 23 times greater compared to PCPs (OR 22.7, 95% CI: 10.3–50.0, p < 0.0001), controlling for patient age, gender, race, and language. 2) HCC screening: 72% (708) of patients required annual HCC screening; only 55% (386) received it. 46% (116) missed HCC screening because physicians did not order it and 54% (136) because patients missed appointments. In the multivariate model, the odds of GIs conducting annual HCC screening were 10 times greater compared to PCPs (OR 9.6, 95% CI: 6.1–15.0, p < 0.0001). 3) Liver Biopsy Adherence: 34 (35%) of 96 patients did not undergo necessary liver biopsies to guide treatment decisions. Of these, 27 (82%) were due to physician failure to order liver biopsies. Six (18.2%) were due to patient factors (i.e. refusal to undergo liver biopsy or loss to follow up). 4) Timely ALT Assessment: Of the 389 inactive carriers, 110 (28%) did not have at least annual ALT assessment. Of these, 53 (48%) were due to physician non-adherence, and 57 (52%) were due to patient noncompli-ance. In the multivariate model, GIs had 3 times greater odds of monitoring at least annual ALT compared to PCPs (OR 2.8, 95% CI: 1.6–4.8, p = 0.0009). 5) Assessment for co-infection: 35% were not tested for hepatitis A immunity. 54% and 24% of patients were not tested for HIV and hepatitis C co-infection, respectively. CONCLUSIONS: In this cohort, adherence to AASLD guidelines for CHB management is poor, particularly in treatment of eAg negative hepatitis, timely HCC and ALT monitoring, liver biopsy, and testing for co-infection.

Disclosures:

Raymond T. Chung - Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support: Gilead, Merck, Mass Biologic, Gilead

The following people have nothing to disclose: Ying Wu, Kara B. Johnson, Joanna Lopez, Hui Zheng, Giorgio Roccaro, Anthony Muiru, Nneka Ufere, Omar Kattan

903

  1. Top of page

Changing the face of chronic Hepatitis B. Final report of the Master-B Italian cohort

Giuseppina Brancaccio1, Alessandra Nardi2, Tiziana G. Giuberti3, Pietro Andreone4, Gioacchino Angarano5, Massimo Fasano6, Fabio Levantesi7, Gabriella Verucchi8, Giovanna Fattovich9, Marco Massari10, Sergio Maimone11, Carlo Contini12, Caius Gavrila2, Giovanni B. Gaeta1;
1Infectious Diseases, Second University, Naples, Italy; 2Mathematics, University Tor Vergata, Rome, Italy; 3Infectious Diseases, University Hospital, Parma, Italy; 4Clinical Medicine, University Hospital, Bologna, Italy; 5Infectious Diseases, University Hospital, Bari, Italy; 6Infectious Diseases, University Hospital, Foggia, Italy; 7Internal Medicine, Hospital, Bentivoglio, Italy; 8Infectious Diseases, University Hospital, Bologna, Italy; 9Gas-troenterology, University Hospital, Verona, Italy; 10Infectious Diseases, Hospital, Reggio Emilia, Italy; 11Internal Medicine, University Hospital, Messina, Italy; 12Infectious Diseases, University Hospital, Ferrara, Italy

Background: Chronic HBV infection is still a major health problem in Europe, intensified by increasing immigration from endemic areas. The Master-B study was aimed at defining the current profile of chronic HBV-infected individuals and their long-term clinical outcome. Methods: Consecutive HBsAg-posi-tive patients seen in 77 Italian specialized centers were enrolled from June 2009 to December 2011, using an electronic CRF. HIV-positive patients were excluded. Follow- up data are recorded at least twice a year. We present the baseline characteristics from the final database of 2920 patients. Results: Males were 68.6%; age 49.4±14.3; BMI 25.3±3.8; 26.7% were immigrants, mainly from Eastern Europe, Asia or Africa. Laboratory features included : mean ALT 64±163; 12.3% HBeAg-positive; anti-HDV in 159/1936 (pos/tested; 8.2%) and anti-HCV positive in 81/2170 (3.7%), alcohol use (>3 drinks/day) in <3%; 41.9 % had undergone liver biopsy. Overall, 22% of the patients had cirrhosis, 29% of whom with decompensation, 58.3% chronic hepatitis and 19.5% were inactive carriers. As compared with Italian patients, immigrants were younger (37±11 vs 53.4±13.1 P<0.001), more frequently HBeAg-positive (23.4% vs 8.2% P<0.001), anti-HDV-positive (10.9 % vs 7.2 %; P<0.02) and less frequently had undergone liver biopsy. Previous antiviral treatment was recorded in 33% of the cases and at the time of enrolment 35% of the patients were being treated with antivirals (50% of cir-rhotics). Conclusions: Chronic HBV infection shows an evolving burden due to the growing cohort of non-Italian patients, who show higher rates of HBeAg or presence of anti-HDV. There are still barriers to access medical care for cirrhotic patients since 50% of them did not receive antiviral treatment when first seen in the specialized centers.

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, Tiziana G. Giuberti, Gioacchino Angarano, Massimo Fasano, Fabio Levantesi, Gabriella Verucchi, Giovanna Fattovich, Marco Massari, Sergio Maimone, Carlo Contini, Caius Gavrila

904

  1. Top of page

Large-scaled Surveillance of Safety and Effectiveness of Entecavir in Korean Patients with Chronic hepatitis B

Chang Wook Kim1, Kyungha Yu2, Myunghoon Kim2, Hee Yeon Kim1, Chang Don Lee1, Heon Ju Lee3;
1Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Bristol-Myers Squibb, Seoul, Republic of Korea; 3Internal Medicine, Yeungnam University, Daegu, Republic of Korea

BACKGROUND/AIM: A large-scaled post marketing surveillance study was carried out to investigate safety and efficacy profile and to analyze the factors which are considered to affect safety and efficacy of entecavir (ETV) in Korean patients with chronic hepatitis B in real life setting. METHODS: From 132 institutions, 3,444 patients were enrolled from May 2006 to May 2012 and collected data. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events(AEs). Laboratory test and overall efficacy were evaluated for efficacy assessment in patients treated with ETV more than 16 weeks. Statistical analyses were conducted to identify the factor affecting on safety and efficacy of ETV. RESULTS: Of the 3,444 patients, 3,367 patients were evaluated for safety and 3,115 patients for efficacy assessment. Totally 380 AEs were reported in 255 (7.57%) cases and events associated with gastrointestinal system such as heartburn, dyspepsia, nausea and epigastric pain were commonly observed AEs. 67 adverse drug reactions (ADRs) which cannot be excluded the causality with ETV therapy were reported in 54 (1.6%) cases. Unexpected AEs were 253 events in 188 (5.58%) case. 19 serious AEs such as hepatoma, ascites, intraabdominal hemorrhage, gastrointestinal bleeding, cholan-gitis, sepsis and hepatic encephalopathy were reported in 9 (0.27%) patients and all of those were reported as 'probably not related to ETV' according to physician's evaluations. The factors of 'medical history' and 'concomitant medication' influence on the incidence rate of AE. In efficacy evaluation, overall efficacy rate was 96.53% (3,007/3,115 patients). Liver function markers such as albumin and bilirubin were improved after ETV therapy. CONCLUSIONS: This large-scaled post marketing surveillance study of patients treated with entecavir showed that entecavir was well tolerated and clinically effective in Korean patients with chronic hepatitis B in real life.

Disclosures:

Chang Wook Kim - Consulting: Gilead; Grant/Research Support: BMS, Boehringer Ingelheim, Pharmicell; Speaking and Teaching: BMS, GSK, Dae-woong

Kyungha Yu - Employment: Bristol-Myers Squibb Myunghoon Kim - Employment: BMS

The following people have nothing to disclose: Hee Yeon Kim, Chang Don Lee, Heon Ju Lee

905

  1. Top of page

Clinical and virological factors that predict post partum flares in pregnant women with chronic HBV

Michelle Giles3,4, Kumar Visvanathan2,8, Sharon R. Lewin4,1, Timothy Spelman6, 1, Stephen Locarnini7, Scott Bowden7, Joe Sasadeusz5,1;
1Infectious Diseases Department, Alfred Health, Melbourne, VIC, Australia; 2Infectious Diseases, Monash Health, Melbourne, VIC, Australia; 3Infectious Diseases, Royal Women's Hospital, Melbourne, VIC, Australia; 4Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia; 5Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC, Australia; 6Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia; 7Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia; 8Medicine, Melbourne University, Melbourne, VIC, Australia

Background Pregnancy is associated with marked immunologi-cal changes; the effects of which on virological and biochemical markers in women with chronic HBV are poorly understood. The aim of this study was to assess the impact of pregnancy on HBV viral load, HBeAg status and liver inflammation during pregnancy and post partum. Methods Women with HBV were recruited during early pregnancy. Demographic and clinical data were collected together with virological and biochemical parameters at 4 time points: early and late pregnancy and post partum between 6 and 12 weeks and at 12 months. Outcomes analysed included flares of hepatitis post-partum (defined as twice the upper limit of normal ALT or twice baseline if ALT was abnormal at baseline), HBV viral load changes and HBeAg seroconversion. Results 126 women were recruited, 18/126 had no post partum bloods. 71% had a vaginal birth, 89% reported some breastfeeding and 6 women took antivirals to reduce perinatal HBV transmission. All neonates received birth dose hepatitis B vaccine and immunoglobulin. One HBV transmission occurred in a woman with a viral load of >log 8 IU/mL who declined antiviral therapy. 28/126 (21%) met our definition of a post partum flare. On univariate analysis these women were more likely to be younger, HBeAg positive and in their first pregnancy. On multivariate analysis HBeAg positivity at baseline and decreased parity were associated with an increased risk of a post partum flare. Conclusion A significant proportion of women (both HBeAg negative and HBeAg positive) have a post-partum flare. HBeAg status and lower parity were significant risk factors for a flare. Clinicians need to be aware of this phenomenon so women at the highest risk can be appropriately identified for close monitoring in the post natal period.

Predictors of post partum flare

Table 5. 
PredictorIncidence risk ratio (95% CI) p valueAdjusted Incidence risk ratio
ALT at baseline0.99(0.99–1.00)0.21 
Quantitative surface antigen1.00 (0.99–1.00)0.77 
HBeAg+ at baseline2.51 (1.32–4.75)0.0052.19(1.13–4.22)0.02
Country of birth (Vietnam vs other)1.26 (0.64–2.46) 0.50 
Gravida0.59 (0.40–0.85) 0.005 
Quantitative eAg1.00(0.99–1.00)0.65 
Parity0.55 (0.36–0.82) 0.0040.56 (0.37–0.85) 0.006
Year of HBV diagnosis (between 1990–1999 compared with pre 1990)0.23 (0.06–0.85) 0.03 
HBeAb+0.42(0.22–0.81)0.01 
Viral load1.06(1.01–1.1210.02 

Disclosures:

Sharon R. Lewin - Advisory Committees or Review Panels: Gilead Sciences, Gilead Sciences, Gilead Sciences, Gilead Sciences; Grant/Research Support: Gilead Sciences, Gilead Sciences, Gilead Sciences, Gilead Sciences

Stephen Locarnini - Consulting: Gilead, Bristol-Myers Squibb, Merck Sharpe and Dohme; Employment: Melbourne Health

Joe Sasadeusz - Grant/Research Support: Roche, Gilead; Speaking and Teaching: Gilaed, Merck

The following people have nothing to disclose: Michelle Giles, Kumar Visvanathan, Timothy Spelman, Scott Bowden

906

  1. Top of page

Tenofovir rescue therapy after multiple nucleos(t)ide analogue treatment failure in chronic hepatitis B patients

Hyo Jin Kim, Ju-Yeon Cho, Geum-Youn Gwak, Yong-Han Paik, Moon Seok Choi, Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo, Joon Hyeok Lee;
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Background: The efficacy of tenofovir disoproxil fumarate (TDF) for treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues is not well defined, especially in Asian countries. Aims: To investigate the efficacy and safety of TDF rescue therapy in CHB patients after multiple NAs treatment failure. Methods: Fifty-two CHB patients who had prior failure with two or more NAs and were switched to TDF containing regimen were retrospectively analyzed. The efficacy and safety assessment included hepatitis B virus (HBV) DNA undetectibility, HBeAg seroclearance, normalization of ALT, changes of serum creatinine and phosphorus level. Results: The median age was 50 years (range 23–65). Thirty-nine patients (75.0%) were male, and 48 patients (92.3%) were positive for HBeAg. The mean HBV DNA level at baseline was 5.4 ± 1.76 log 10 IU/mL. At baseline, genotypic resistances to LAM, LAM/ADV, LAM/ETV and LAM/ADV/ETV were present in 22 (42.3%), 8 (15.4%), 17 (32.7%) and 2 (3.8%) patients, respectively. After median duration of 34.5 months (range, 6–55 months) of TDF containing treatment, the cumulative probabilities of achieving complete virologic response (CVR) were 51.8%, 74.2%, 90.0% and 96.7% at 12, 24, 36 and 48 months, respectively. Seroclearance of HBeAg occurred in 7 of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Higher levels of HBV DNA at baseline were significantly associated with a decreasing rate of achieving CVR (p value for trend = 0.03). However, treatment efficacy of TDF was not affected by either TDF monotherapy or combination therapy with LAM or ETV, as well as by mutations associated with resistance to NAs. No significant adverse events were observed during TDF therapy except one patient who developed hypophosphatemia. Conclusions: TDF is an efficient and safe rescue therapy in CHB patients after multiple NAs treatment failure. Keywords: Tenofovir, chronic hepatitis B, treatment failure, resistance

Disclosures:

The following people have nothing to disclose: Hyo Jin Kim, Ju-Yeon Cho, Geum-Youn Gwak, Yong-Han Paik, Moon Seok Choi, Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo, Joon Hyeok Lee

907

  1. Top of page

Oral Antiviral Prophylaxis is Effective in Preventing HBV Reactivation in HBsAg-Positive Systemic Lupus Erythe-matosus Patients Undergoing Immunosuppressive Therapy

Sheng-Shun Yang1,4, Woan-Tyy Lin1, Der-Yuan Chen2,4, Chi-Sen Chang3,5, Hong-Zen Yeh1,4;
1Division of Gastroenterology & Hepa-tology, Taichung Veterans General Hospital, Taichung, Taiwan; 2Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; 3School of Medicine, Chung-Shan Medical University, Taichung, Taiwan; 4Department of Medicine, National Yang-Ming University, Taipei, Taiwan; 5Depart-ment of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

Purpose: The interplay between hepatitis B virus (HBV) infection and systemic lupus erythematosus (SLE) was rarely reported. We investigate HBV infection status and the role of antiviral agents on HBV reactivation in SLE patients (pts). Methods: We retrospectively analyzed the recorded electronic database on virologic, serological and biochemical evidence of HBV reactivation in HBsAg-positive & anti-HBc-positive SLE pts undergoing immunosuppressive therapy from Jan 2001 to Dec 2012 at one medical center. Results: A total of 44 SLE pts (34 women, 10 men, mean age 36.3 y/o; women 33.7, men 45.0) had detected HBsAg positivity on records from 916 pts who had been received HBsAg/IgG anti-HBc test. In this period 3,236 pts were diagnosed with SLE which approved by obtaining major illness certificate from Bureau of National Health Insurance. The prevalence of HBsAg-positive carriers was 4.8% among SLE pts which was far below that in general population in Taiwan (greater than 8%, WHO). Of note, only one out of 44 was born after commencing universal hepatitis B vaccination program (Jul 1984) in Taiwan (prevalence 1/130 = 0.8%). Four of 44 pts (9%) had HBsAg seroreversion on follow-up. 180 pts had anti-HBc-positive /c or /s anti-HBs positivity (19.7%), of them 5 in 20 (25%) HBsAg/anti-HBs-negative developed ALT flare (defined as ALT greater than 100 U/L) more than once on follow up either under Prednisolone (Pd) or other immunosuppressive agents. In contrast, 21 of 44 HBsAg-positive (48%) had ALT flares for one up to seven times on follow-ups. Of them, eight experienced severe acute exacerbation of HBV defined as ALT greater than 10X ULN with total biliru-bin greater than 2.0 mg/dL or PT prolongation greater than 3 seconds to control. Two pts died of fulminant hepatic failure inspite of antiviral rescues, both were HBeAg-negative men (73.8 & 54.4 y/o), one under low dose Pd plus Azathioprine (HBsAg seroreverter), while the other taking Pd 1 7.5 mg & Cyclophosphamide 75 mg daily. Six of these eight pts (oldest 48.8 y/o) recovered from severe HBV flares after oral antiviral treatment, while 4 of 44 HBsAg-positive pts taking prophylactic antiviral agent did not encounter any episode of HBV flare. Conclusions: Prevalence of HBsAg-positive carriers in SLE pts was lower than that in general population in Taiwan. Universal hepatitis B vaccination was effective in reducing HBV carriers in SLE pts. HBV reactivation and HBsAg seroreversion were very common in HBsAg-positive and anti-HBc-positive SLE pts receiving immunosuppressive therapy with potential life threatening, and antiviral prophylaxis was effective in preventing HBV reactivation in HBsAg-positive subjects.

Disclosures:

The following people have nothing to disclose: Sheng-Shun Yang, Woan-Tyy Lin, Der-Yuan Chen, Chi-Sen Chang, Hong-Zen Yeh

908

  1. Top of page

IL28B genotype in HDV chronic patients correlates with unfavourable outcome but not with response to IFN treatment

Raffaella Romeo1, Alessio Aghemo1, Giovanni Casazza2, Enrico Galmozzi1, Floriana Facchetti1, Matteo A. Manini1, Elisabetta Degasperi1, Massimo Colombo1;
1Gastroenterology Unit, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 2Dipatimento di Scienze Biomediche e Cliniche "L. Sacco",, University of Milan, Milan, Italy

Interferon (IFN) treatment is so far the only registered drug for chronic HDV infection but the proportion of sustained virologic response is still poor. Interleukin 28 rs12979860 (IL28B) polymorphisms have been associated to interferon-induced viral clearance in patients with chronic hepatitis C. Aim: to explore whether IL28B polymorphism could play a role on IFN response and/or on clinical outcome in chronic HDV infection. Patients and methods: 136 consecutive anti-HDV positive patients (93 males, mean age 56 yrs) with chronic hepatitis, followed for a mean of 20,6 yrs (2–41). 93 patients (68%) had a previous history of treatment with standard IFN for a mean of 20 months (range 6–94). Mean follow-up after IFN treatment was 14 yrs (4–21). IL28B genotype was obtained by Taqman SNP genotyping assay on fresh blood samples. Results: 50 patients (37%) had genotype CC, 68 (50%) had genotype CT and 18 (13%) had genotype TT. Among IFN treated patients, the distribution of genotypes was CC in 32 (34%), CT 48 (52%), TT 13 (14%). There were no differences among genotypes in terms of age, gender, prevalence of cirrhosis at baseline, number of treated patients and treatment duration. Moreover, there were no differences in terms of biochemical response (22%, 25% and 15%, respectively; p=ns), virological response (12%, 10%, 7%, respectively; p=ns) and sustained virological response (19%, 25%, 31%, respectively; p=ns). When IL28B genotypes were analyzed according to clinical outcome, TT appeared to be significantly and independently associated to the risk of HCC development (p= 0.0069; OR 5.72; 95% CI 1.52–21.51) and liver decompensation (p=0.035; OR 2.91; 95% CI 0.962–8.843). When the clinical outcome of IL28B TT was analyzed against IL28B CC and IL28B CT taken together, again IL28B TT appeared as significantly and independently associated to the risk of developing HCC (p=0.0081; OR 4.37; 95% CI1.467–13.016) and liver decompensation (p=0.03; OR 2.964; 95% CI 1.08–8.14).Conclusion: IL28B is not a predictor of IFN response in chronic HDV infection. However, the IL28B TT genotype strongly correlates with the occurrence of unfavourable outcomes such as HCC and liver decompensation.

Disclosures:

Alessio Aghemo - Advisory Committees or Review Panels: Roche, Janssen; Grant/Research Support: Gilead Sciences, Roche; Speaking and Teaching: MSD, Roche,Janssen

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEYERS-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

The following people have nothing to disclose: Raffaella Romeo, Giovanni Casazza, Enrico Galmozzi, Floriana Facchetti, Matteo A. Manini, Elisabetta Degasperi

909

  1. Top of page

The natural long-term outcome of genotype-D infection in inactive carriers and HBeAg negative low viremic active carriers: benign one direction towards spontaneous HBsAg clearance

Lidia Surace1, Piero Colombatto1, Filippo Oliveri1, Francesco Mori-coni1, Daniela Cavallone1, Barbara Coco1, Pietro Ciccorossi1, Beatrice Cherubini1, Gabriele Ricco1, Carlotta Rastelli1, Veronica Romagnoli1, Ferruccio Bonino2, Maurizia R. Brunetto1;
1Hepatol-ogy Unit, University Hospital of Pisa, Pisa, Italy; 2General Medicine 2 Unit, University Hospital of Pisa, Pisa, Italy

Background & aims. Studies of the long term outcome of HBV carriers with inactive infection, defined after stringent (at least one year) follow-up are missing. We studied a large cohort of HBeAg negative HBsAg carriers with serum HBV-DNA persistently <20,000 IU/ml (active carriers 1, AC 1) or <2,000 IU/ml (inactive carriers, IC) Methods. Out of 124 carriers with serum HBV-DNA <20,000 IU/ml, 101 (51 M / 50 F, median age 48 yrs, range: 23–80 yrs) consented to be followed-up (median 58 months, range 17–172). Their baseline (BL) classification as AC1 or IC was achieved after the first year follow-up, where ALT and HBV-DNA were tested at least every 3 months and HBsAg serum levels (Architect-QT) every 6 months. The viral and clinical profiles were analyzed 2–4 times per year thereafter and factors predicting the end of follow-up (EOF) transitions between HBV infection phases and/or HBsAg loss were studied by multivariate analysis (SSPS, version 20). Results. BL and EOF characteristics of 65 IC and 36 AC1, are shown in the table (data expressed in median values). At EOF 13 of the 65 (20%) IC lost HBsAg and 52 (80%) remained IC. Out of 36, AC13 (8.3%) lost HBsAg, 22 (61%) became IC, 10 (27.8%) remained AC1 and 1 (2.8%) showed hepatitis B reactivation. AC1 to IC transition was associated with lower HBsAg BL (mean Log10 UI/mL: 2.74 vs3.30, p=0.045). HBsAg loss was associated with lower HBV-DNA BL (mean Log10 UI/mL: 1.54 vs 2.44, p=0.002), lower HBsAg BL (0.15 vs 2.67, p<0.001) and greater delta-Log HBsAg/year (mean: 0.25 vs 0.09, p=0.002);at logistic-regression analysis only HBsAg BL remained statistically significant (p<0.001). Conclusions. Inactive and low viremic active genotype D, HBV carriers, identified by 1 year /every 3 month serum HBV-DNA tests, have long term (5 years) benign clinical outcomes associated with high rates of HBsAg loss (20% and 8.3%, respectively). HBV reactivation is an unusual event, observed in only one AC1 (<1% overall).

BL and EOF characteristics of 65 IC and 36 AC1

Table 6. 
Phase of infectionAgeHBV-DNA BL (Logl0 UI/mL)ALT (LVL)HBsAg BL (LoglO UI/mL)HBsAg EOF (Logl0 UI/mL)Overall follow-up (months)Post-BL follow-up (months)Delta-Log HBsAgDelta-Log HBsAg/year
IC(34 M, 31 F)511.65212.152.0050.531.30.160.05
AC1 (17 M, 19 F)433.29222.992.1067.446.20.760.08

Disclosures:

Filippo Oliveri - Consulting: Bristol-Myers Squibb EMEA sarl

Ferruccio Bonino - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: Gilead, Novartis, BMS

Maurizia R. Brunetto - Speaking and Teaching: Roche, Gilead, Schering-Plough, Bristol-Myers Squibb, Abbott, Roche, Gilead, MSD, Novartis

The following people have nothing to disclose: Lidia Surace, Piero Colombatto, Francesco Moriconi, Daniela Cavallone, Barbara Coco, Pietro Ciccorossi, Beatrice Cherubini, Gabriele Ricco, Carlotta Rastelli, Veronica Romagnoli

910

  1. Top of page

Relapse rates in chronic hepatitis B naïve patients after entecavir discontinuation in real life

Ezequiel Ridruejo1,2, Sebastian Marciano3, Omar A. Galdame3, María Virginia Reggiardo4, Alberto Muñoz5, Raúl Adrover6, Daniel R. Cocozzella6, Nora C. Fernández7, Claudio R. Estepo8, Manuel Mendizabal2, Gustavo Romero5, Diana Levi5, Teresa Schroder8, Silvia Paz8, Hugo Fainboim8, Oscar G. Mandó1, Adrian Gadano3, Marcelo O. Silva2;
1Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno" CEMIC, Buenos Aires, Argentina; 2Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Argentina; 3Hepatology and Liver Transplant Unit, Hospital Italiano, Buenos Aires, Argentina; 4Hospital Provincial del Centenario/Sanatorio Americano, Rosario, Argentina; 5Hospital Bomorino Udaondo, Buenos Aires, Argentina; 6Centro de Hepa-tologia, La Plata, Argentina; 7Hospital Britanico, Buenos Aires, Argentina; 8Hospital Francisco J Muñiz, Buenos Aires, Argentina

Background: Registration studies showed Entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates in chronic hepatitis B naïve patients after treatment discontinuation in routine clinical practice have not been well established. Aim: to evaluate sustained virological response 6 or 12 months after ETV discontinuation in real life. Methods: We evaluated sustained virological response, relapse rates and predictors of relapse in chronic hepatitis B naïve HBeAg positive and negative patients treated with ETV for more than 6 months in 8 centres in Argentina. Treatment duration was defined according to national and international guidelines. Virological relapse was defined as an increase in serum HBV DNA to >2000 IU/mL after discontinuation of treatment. T Student, x2 and logistic regression tests were used for statistical analysis. P <0.05 was considered statistically significant. Results: 169 consecutive patients were treated with ETV for 183 ±81 weeks between January 2005 and March 2013. 61% were HBeAg positive, 23% were cirrhotics (11 patients with decompensated cirrhosis before treatment), mean HBV-DNA levels were 6,88 ±1,74 log10 IU/ml, and mean ALT levels were 139 ±231 IU/ml. 156 (92%) patients became HBV DNA undetectable; 74 (71%) became HBeAg negative and 71 (68%) antiHBe positive, after 70 ±42 weeks of treatment; 23 (14%) patients became HBsAg negative and 22 (13%) antiHBs positive, after 96 ±46 weeks of treatment. At the end of the study, 36 patients discontinued treatment. One due to breakthrough associated to resistant variants, and 35 (20%) due to sustained virological response at 6 or 12 months after ETV. Thirty three of these patients developed HBeAg/antiHBe sero-conversion and 18 HBsAg/antiHBs seroconversion. Mean off treatment duration was 80 ±52 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a mean 51 ±34 weeks off treatment, 3 of them showed HBeAg seroreversion and 4 lost antiHBe. No patient with HBsAg/anti-HBs seroconverters developed virological relapse. None of baseline and on treatment predictors (sex, race, age, baseline HBV DNA, fibrosis stage, ETV treatment duration, week of HBV DNA clearance) evaluated were associated with virological relapse. The 9 patients with virological relapse received treatment with ETV (1 associated with adefovir) and became HBV DNA undetectable thereafter. Conclusion: Discontinuation of ETV therapy is safe in patients who achieved HBsAg/antiHBs seroconversion. Due to the risk of HBV DNA relapse, close follow up is recommended for patients with HBeAg/antiHBe seroconversion who discontinue ETV.

Disclosures:

Hugo Fainboim - Speaking and Teaching: Bristol Myers Squibb

Marcelo O. Silva - Advisory Committees or Review Panels: Schering Plough, Vertex, Abbott; Board Membership: BMS; Grant/Research Support: Schering Plough, BMS; Speaking and Teaching: Schering Plough, BMS, MSD

The following people have nothing to disclose: Ezequiel Ridruejo, Sebastian Mar-ciano, Omar A. Galdame, María Virginia Reggiardo, Alberto Muñoz, Raúl Adrover, Daniel R. Cocozzella, Nora C. Fernández, Claudio R. Estepo, Manuel Mendizabal, Gustavo Romero, Diana Levi, Teresa Schroder, Silvia Paz, Oscar G. Mandó, Adrian Gadano

911

  1. Top of page

Comparison of Demographic, Virologic, and Outcome Characteristics of People with Chronic Hepatitis B in a Major US Urban Center

Thomas M. Leventhal1, Coleman Smith1, Qi Wang2, Mohamed A. Hassan1;
1Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN; 2Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN

Background/Aims: Immigrants to the United States represent the largest population with chronic hepatitis B (CHB). The state of Minnesota is unique, with large immigrant populations of Southeast Asians and East Africans. In this study we compared demographic, virologic, laboratory, imaging, and outcome data between various immigrant groups and those who are US-born. Methods: We retrospectively evaluated charts of persons with CHB seen in hepatology outpatient clinics at the University of Minnesota between January 1 st, 2007 and December 31 st, 2010. Results: Of the 400 adult persons with CHB evaluated, 58% were males and 42% females. Average age was 40.2 years for females and 42.2 years for males. Approximately 26% of persons were Southeast (SE) Asian, 38% East African, 13% East Asian, 12% US-born, and 7% West African. Household exposure to Hepatitis B was more common amongst those from Asia compared to those from Africa (P<0.0001). When compared to immigrant populations, US-born patients were most likely to have IV drug use, high-risk sexual practices, or unknown exposures for contracting CHB (P<0.0001). HBeAg-positivity rates were highest in those from Southeast (29%) and East (37%) Asia and were lower in those from East (8%) and West (4%) Africa. HBeAg-positivity was more common in persons < 30 years old (32% Vs. 13%; P<0.0001). Mean HBV DNA quantitative log IU levels were significantly higher in Southeast Asians (4.5 log IU) and East Asians (4.4 log IU) compared to those from East Africa (2.9 log IU) and West Africa (2.7 log IU). There was a trend of higher alanine aminotrans-ferase (ALT) levels in Asian populations on presentation. Platelet levels of < 140,000 corresponded with clinical diagnosis of cirrhosis (OR, 51.8; 95% CI, 23.9–112.3; P<0.0001). Over this study period 79 of 400 (19.8%) patients were diagnosed with cirrhosis. Patients who were US-born and those from SE Asia were most likely to both present with and develop cirrhosis. Patients from Southeast Asia and East Africa where least likely to have had screening imaging tests (P<0.009), and those from East Africa had the lowest mean average clinic visits per year (1.0 visits/year, P<0.001). 19 persons in the study were diagnosed with hepatocellular carcinoma (HCC), and the majority of these were from Southeast Asia (9) or US-born (7). CONCLUSIONS: From this retrospective study, we found that persons seen in clinic from Southeast Asia were more likely to have active Hepatitis B, more advanced liver disease at presentation, and an increased risk of developing HCC, while patients from East Africa were less likely to receive adequate screening and follow up.

Disclosures:

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

Mohamed A. Hassan - Speaking and Teaching: GILEAD

The following people have nothing to disclose: Thomas M. Leventhal, Qi Wang

912

  1. Top of page

Prolonging antiviral therapy after pregnancy for prevention of perinatal HBV transmission does not abrogate post-partum flares

Vi Nguyen1, Pok Kern Tan1, Astrid-Jane Greenup1, Anne L. Glass1, Scott Davison1, Ushmi Chatterjee3, Susan Holdaway2, Dev Sama-rasinghe2, Stephen Locarnini4, Miriam Levy1,3;
1Liverpool Hospital, Sydney, NSW, Australia; 2Westmead Hospital, Sydney, NSW, Australia; 3University of New South Wales, Sydney, NSW, Australia; 4Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia

Background/Aim: Information on the nature of post-partum flares (PPF) in the setting of hepatitis B virus (HBV) infection is limited. Antepartum antiviral therapy is administered to prevent perinatal transmission, but there are concerns this may exacerbate PPF. The aim of this study was to examine whether extending antiviral therapy beyond birth influences the post-partum course. Methods: Pregnant women with HBV and a high baseline viral load (>log7 IU/ml) were prospectively recruited from multiple tertiary centres in Sydney, Australia from 2007–2013. From 2007–2009 lamivudine was administered from 32 weeks(wks) gestation and continued for an average of 2wks post-partum. Due to lamivudine resistance concerns tenofovir was used from 2010, and post-partum treatment extended to 12wks from 2011 in an effort to abrogate flares. Consenting women who declined treatment were included in a natural history arm. Virological, clinical & biochemical parameters were followed. Outcomes by post-partum treatment duration were assessed in three groups: Group 1 =treatment <4wks, Group2=treatment >4wks, and Group3=natural history arm. Results: Data from 91 pregnancies in 83 women where at least two ALT measurements post-partum were available were included for analysis. Median age was 29 years, baseline viral load was log7.85 IU/ml and ALT 25 U/ml(range 6–521 U/ml). Median follow-up was 48wks post-partum. Median post-partum treatment duration was 2wks for Group1 (n= 42), and 12wks for Group2(n=35). 14 women had no treatment. Flare rates; Group1 =21/42(50%), Group2 = 14/35(40%), and Group3=4/14(29%) were not significantly different [p=0.34]. The median time of flare onset was similar: 8/10/9 wks for Groups 1/2/3 respectively [p=0.49]. Treatment duration also had no impact on flare severity, however did appear to influence the time to flare resolution [F(2,21)=5.86,p=0.01]. Post-hoc comparisons revealed the mean duration of flares in Group2 (M=16.5wks,SD=10.07) were significantly longer than those observed in Group1 (M=7wks,SD=4.04) and Group3 (M=6.5wks,SD=3.00). No clinical parameters could reliably predict a flare, including the type of antiviral used and genotype. Six cases of HBeAg seroconversion were observed: 1/4/1 in Groups 1/2/3 respectively. HBeAg seroconversion rates were not associated with treatment duration nor the occurrence of a PPF. Conclusion: Post-partum flares in HBV are common. The majority of flares arise early after delivery, are often mild in severity, and usually spontaneously resolve. Extended antiviral therapy does not appear to the affect the rate or severity of PPF, nor does it improve HBeAg seroconversion rates, while it may prolong flare duration.

Disclosures:

Stephen Locarnini - Consulting: Gilead, Bristol-Myers Squibb, Merck Sharpe and Dohme; Employment: Melbourne Health

Miriam Levy - Grant/Research Support: Gilead

The following people have nothing to disclose: Vi Nguyen, Pok Kern Tan, Astrid-Jane Greenup, Anne L. Glass, Scott Davison, Ushmi Chatterjee, Susan Holdaway, Dev Samarasinghe

913

  1. Top of page

Association of IL28B polymorphisms with peginterferon treatment response in Chinese Han patients with HBeAg-positive chronic hepatitis B

Haiqing Wu1, Gangde Zhao1, Fangxing Qian2, Kehui Liu1, Jing-dong Xie1, Huijuan Zhou1, Jie Xu3, Yumin Xu1, Yan Han1, Qing Xie1, Hui Wang1;
1Department of Infectious Diseases, Rui Jin Hospital, School of medicine, Shanghai Jiao Tong University, Shang hai, China;2Department of Infectious Diseases, Shanghai Changn-ing District Center Hospital, Shang hai, China; 3Department of Infectious Diseases, Shanghai Third People's Hospital, School of medicine, Shanghai Jiao Tong University, Shang hai, China

Aims: To investigate whether IL28B polymorphisms could affect the treatment response to PEG-IFN in chronic hepatitis B (CHB) patients in the Chinese Han population. Methods: A total of 212 HBeAg positive patients treated with PEG-IFN monother-apy were enrolled in the retrospective case-control study. Genotype analysis was performed for IL28B rs12980275, rs12979860 and rs8099917 using the MassArray system. Response was defined as cases showing normal ALT levels, HBV DNA level < 200 IU/mL and HBeAg seroconversion after 48 weeks of PEG-IFN therapy. Results: The patients were infected with hepatitis B virus (HBV) genotype B (44.8%) and C (55.2%) with a total response rate of 34.9%. For the three SNPs, there were significant differences between the response (R) and non-response (NR) groups both in allele frequencies and genotype distributions. IL28B genotype was independently associated with R for AA versus N-AA (OR 2.70, P=0.015) at rs12980275 after adjustment for sex, age, HBV genotype, baseline levels of HBV DNA and ALT. There were similar results for rs12979860 CC versus N-CC (OR 2.56, P=0.021) and rs8099917 TT versus N-TT (OR 2.80, P=0.015) respectively. Furthermore, one block formed by rs12980275 and rs12979860 was identified in this study. In multivariate analyses, the most common haplotype A-C was independently associated with high rates of R (OR 2.53, P=0.015). Conclusions: Our study suggested that genetic variations in IL28B may play a critical role in efficacy of PEG-IFN treatment in HBeAg-positive CHB patients in Han Chinese. javascript:setNextPage('TITLE_BODY')

Disclosures:

The following people have nothing to disclose: Haiqing Wu, Gangde Zhao, Fangxing Qian, Kehui Liu, Jingdong Xie, Huijuan Zhou, Jie Xu, Yumin Xu, Yan Han, Qing Xie, Hui Wang

914

  1. Top of page

Fibrosis progression in chonic hepatitis B is biphasic and influenced by multiple single-nucleotide polymorphisms

Willem Pieter Brouwer1, Adriaan J. van der Meer1, Milan J. Sonn-eveld1, Andre Boonstra1, Zwier M. Groothuismink1, Annemiek A. van der Eijk1, Robert J. de Knegt1, Bettina E. Hansen1,2, FieboJ. ten Kate3, Harry L. Janssen4,1;
1Gastroenterology & Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands; 2Public Health, Erasmus Medical Center, Rotterdam, Netherlands; 3Pathol-ogy, Erasmus Medical Center, Rotterdam, Netherlands; 4Liver Clinic, Toronto Western and General Hospital University Health Network Toronto, Toronto, ON, Canada

Background & Aims. Little is known about the progression of liver fibrosis in chronic hepatitis B virus (CHB) infected patients. We aimed to assess the dynamics of and factors associated with fibrosis progression in CHB. Methods. All consecutive treat-ment-naïve patients with CHB diagnosed from 1985 to 2012 for whom a liver biopsy was available for scoring by a single experienced pathologist and for whom a serum sample was available for DNA analysis were studied. Fibrosis (Ishak;0–6) was determined and the annual fibrosis progression rate (aFPR) was calculated using the presumed date of infection. Single-nucleotide polymorphisms (SNPs) were selected from the literature and determined using competitive allele-specific PCR. Results. Five-hundred and seventy-eight patients were included; 47/31/19/3% were Caucasian/Asian/Black/other and viral genotype was A/B/C/D/E/unknown in 14/8/11/21/4/42%, respectively. Mean age at biopsy was 34.5 (SD 12.5) and estimated infection duration was 31.1 (SD 12.8) years. Median aFPR was 0.08 units/year (IQR 0.04–0.12). We observed a stable phase during the first 2 decades of infection with a subsequent exponential increase in aFPR. During the stable phase, aFPR was associated with male sex and SNP AQP2 (b=0.502,SE=0.200;p=0.014). During the exponential progression phase, male sex, alcohol abuse and SNPs POLG-2 (AA/AC vs CC;b=0.423,SE=0.195;p=0.031) and GLT8D2 (b=0.205,SE=0.096;p=0.033) were associated with aFPR, while SNP AQP2 did not show an effect (p=0.72). Conclusion. Liver fibrosis progression in CHB is biphasic, with an exponential increase observed after an initial stable phase. While SNP AQP2 was associated with aFPR during the stable phase, SNPs POLG-2 and GLT8D2 were associated with exponential progression, suggesting a shift in the effects of SNPs on fibrosis over time.

Disclosures:

Adriaan J. van der Meer - Speaking and Teaching: MSD

Milan J. Sonneveld - Speaking and Teaching: Roche

Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

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

The following people have nothing to disclose: Willem Pieter Brouwer, Zwier M. Groothuismink, Annemiek A. van der Eijk, Bettina E. Hansen, Fiebo J. ten Kate

915

  1. Top of page

Chronic hepatitis B in pregnancy - can virological, sero-logical and immunological markers during pregnancy predict post delivery hepatic flares?

Ivana Carey, Mary Horner, Matthew J. Bruce, Marie-Ange McLeod, Kosh Agarwal;
Institute of Liver Studies, Kings College School of Medicine at King's College Hospital, London, United Kingdom

The interaction between immune system and HBV is crucial for the outcome of infection. Pregnancy is characterized by state of physiological immune tolerance. The restoration of immune system post delivery might account for hepatic flares in HBV infected patients. Only one study has investigated the relationship between innate immune system activation markers during pregnancy and prediction of hepatitis flares after delivery. IP10 plasma levels were not studied in context of pregnancy. Finding simple diagnostic markers during pregnancy to predict post delivery hepatic flares (HF) allows early management to prevent inflammation related liver damage. Aims: To investigate IP10 plasma levels and variable serological/virological markers (HBsAg levels, HBV DNA, HBV genotype) in pregnant chronic hepatitis B (CHB) patients in 2nd trimester of pregnancy to predict hepatic flare after delivery. Patients: 129 pregnant HBsAg+ patients (median age 30 years, 13% HBeAg+) were seen between September 2011 - April 2013 by liver specialist (1st visit median gestation week 27). 1 patient was treated with tenofovir (TDF) prior to pregnancy and 9 patients started TDF from gestation week 28 to prevent HBV transmission. 63 untreated patients were seen after delivery (median 91 days). 20 (32%) patients had hepatic flare (ALT>40 IU/l and increased twice from pregnancy level) (median ALT 63 IU/l) after delivery. Methods: Plasma IP10, HBsAg, ALT and HBV DNA levels were measured at therapy baseline by ELISA [pg/ml], Abbott ARCHITECT® assay [log10 IU/ml], Auto-Analyser [IU/l] and real-time TaqMan PCR [log10 IU/ml] in 63 untreated patients. The results were compared between patients with hepatic flares (HF) (n=20) and normal ALT post delivery (n=43). HBV genotypes were determined in 43/63 patients with HBV DNA >50 IU/ml by the direct sequencing. Results: HF patients have higher HBV DNA (3.77. vs. 2.66, p=0.01) and IP10 (254 vs. 165, p=0.03), but similar HBsAg and ALT levels during pregnancy. Genotype distribution was: A 12%, B 12%, C 16%, D 10% and genotype E 50% patients. Genotypes B&C were more prevalent in patients with HF (67% genotype B&C patients vs. 22% genotype A, D&E, p=0.03). Only for genotype B&C, HF patients had higher HBsAg than in normal ALT (4.04 vs. 1.65, p=0.05). For all genotypes IP10>200 pg/ml (PPV 80%) and HBV DNA >4log10 IU/ml (PPV 78%) were predicting hepatic flares. Conclusions: High HBV DNA (>4 log10 IU/ml) and IP10 (> 200 pg/ml) levels in 2nd trimester of pregnancy may help predict post delivery pregnancy flares in all HBV genotypes. High HBsAg (>4 log10IU/ml) in genotype B&C patients was associated with post delivery pregnancy flares.

Disclosures:

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

Kosh Agarwal - Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

The following people have nothing to disclose: Mary Horner, Matthew J. Bruce, Marie-Ange McLeod

916

  1. Top of page

Comparative Incidence of Treatment-Emergent Gastrointestinal Disorders in Chronic Hepatitis B Patients on Tenofovir versus Entecavir in Routine Clinical Care in the US

Brett Pinsky1, Timothy Juday2, Shom N. Paul1, Natanya M. Jennings2, Syed Quadri2, Lisa McGarry1;
1Optum, Eden Prairie, MN; 2Bristol-Myers Squibb, Plainsboro, NJ

Background: Incidence of gastrointestinal (GI) disorders in chronic hepatitis B (CHB) patients on tenofovir vs entecavir in US routine clinical care has not been quantified. Objective: To estimate the incidence of GI disorders in CHB patients treated with tenofovir vs entecavir in US routine clinical care. Methods: A retrospective analysis of commercially-insured adults (18–64 years) with CHB and prescription claims for oral entecavir or tenofovir antiviral therapy (01 Jul2005 to 30Sep2011) was conducted using a large US healthcare claims database. Patients were required to be continuously enrolled in the database >6 months before the index date and 6 months after the index date. Incidence of GI disorders was identified, and event-free survival was estimated using Kaplan-Meier techniques with initiation of oral antiviral mediation as the start date. Unadjusted and adjusted incidence rates were estimated using poisson distribution GLM model adjusting for age, sex, geographic region and Quan Charlson comorbidity score. Results: 1,142 CHB patients were treated with either tenofovir (490) or entecavir (652). The mean age was 43.8 years and females comprised about 29% of the study group. The mean Charlson comorbidity scores were similar (both 1.1), but entecavir patients had a higher prevalence of Hep C (12% vs. 8%, p=.018). Over the follow-up period, tenofovir patients had a higher unadjusted incidence of new onset GI disorders than entecavir patients (Fig 1). Adjusted incidence was also higher in tenofovir patients than entecavir patients (7.15 vs 4.63); the difference in adjusted incidence trended towards statistical significance [RR = 1.54, p=0.055]. Conclusions: Over a 2-year period, CHB patients in US routine clinical care treated with tenofovir had a higher incidence of treatment-emergent GI disorders than those treated with entecavir.

Disclosures:

Brett Pinsky - Grant/Research Support: Bristol Myers Squibb

Timothy Juday - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers Squibb

Natanya M. Jennings - Employment: Bristol-Myers Squibb

Syed Quadri - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers Squibb

Lisa McGarry-Consulting: BMS; Employment: Ariad, Optum The following people have nothing to disclose: Shom N. Paul

917

  1. Top of page

Characterization of intrahepatic HBV quasispecies genetic variability within the pre-S region in patients with HBV-related hepatocellular carcinoma

Anye Zhang1, Danny Wong1, Fung-Yu Huang1, James Fung1, Wai-Kay Seto1, Ronnie T. Poon2, Ching-Lung Lai1, Man-Fung Yuen1;
1Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong;2Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong

Background and aim: The association between intraphepatic hepatitis B virus (HBV) quasispecies variability and the development of hepatocellular carcinoma (HCC) is unclear. Previous studies have shown that HBV pre-S deletions are associated with HCC. We aimed to investigate the intrahepatic HBV quasispecies genetic variability within the pre-S region in paired tumor and non-tumor tissues from patients with HBV- related HCC. Methods: Intrahepatic HBV DNA was extracted from the tumor and adjacent non-tumor liver tissues of 13 HCC patients. The HBV pre-S regions were amplified, followed by direct sequencing and clonal sequencing. Quasispecies complexity within the pre-S region, measured by normalized Shannon entropy (Sn), were assessed, while quasispecies diversity, measured by mean genetic distance (d), were analyzed using MEGA5. Phylogenetic trees were constructed from viral quasispecies sequences in the tumor and non-tumor tissues. Com-partmentalization, which indicates non-random quasispecies distribution and virus-host interactions, was assessed using the correlation coefficient test by HyPhy2 software. For each tumor and non-tumor paired samples, existence of compartmentaliza-tion was denoted by p<0.05. Results: In either the tumor or non-tumor tissues, clonal sequencing could detect pre-S deletions in 10/13 patients, while direct sequencing could only detect pre-S deletions in 5/13 patients (p=0.047). HBV quasispecies complexity was significantly lower in the tumor tissues than the non-tumor tissues in both nucleotide level (Sn: 0.8051 vs. 0.9323, respectively; p=0.014) and amino acid level (Sn: 0.7718 vs. 0.8909, respectively; p=0.043). HBV quasispecies diversity was also significantly lower in the tumor tissues than the non-tumor tissues in both nucleotide level (d: 6.99x10–3 vs. 14.19x10–3 substitutions/site, respectively; p=0.048) and amino acid level (13.30x10–3 vs. 24.54x10–3 substitutions/site, respectively; p=0.022). Phylogenetic analysis showed that HBV sequences derived from tumor or non-tumor compartments were separately clustered. Correlation coefficient test showed that compartmentalization of quasispecies occurred in all 13 patients (all p <0.05). Conclusion: A higher frequency of HBV pre-S deletions was identified in HCC patients using clonal sequencing, revealing the existence of minor HBV quasispecies with pre-S deletions which could be missed by direct sequencing. HBV quasispecies complexity and diversity were lower in the tumor tissues, and viral quasispecies were compartmentalized between the tumor and non-tumor counterparts, suggesting selection of pre-S genetic variations in the carcinogenic process.

Disclosures:

James Fung - Speaking and Teaching: Bristol Myers Squibb

Wai-Kay Seto - Advisory Committees or Review Panels: Gilead Science; Speaking and Teaching: Gilead Science

Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc; Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc

Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science

The following people have nothing to disclose: Anye Zhang, Danny Wong, Fung-Yu Huang, Ronnie T. Poon

918

  1. Top of page

Genomic polymorphisms and hepatocellular carcinoma with hepatitis B virus infection in Chinese Han population

Zheng Zeng1, Xian Liu2;
1Peking University First Hospital, Beijing, China; 2Department of Infectious Diseases, Peking University First Hospital, Beijing, China

Objective: To investigate the genomic polymorphisms that association with hepatocellular carcinoma in Chinese patients with hepatitis B virus (HBV) infection. Methods: Genomic DNA was extracted from 465 samples, in which 256 chronic hepatitis B (CHB, Age 48.71 ±5.34, Male/Female 197/59), 209 hepatocellular carcinoma (HCC, Age 49.78±8.72, Male/Female 187/22) with HBV infection (72 HCC without liver cirrhosis (non-LC HCC, Age 50.17±9.41, Male/Female 65/7), 137 HCC with liver cirrhosis (LC-HCC, Age 49.58±8.38, Male/Female 122/15)). The MIT Tagger Server was used to select candidate 384 SNPs from chromosome 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 and 21 according published literatures and gene function pathway. Illumina Gold-enGate SNP chips were used to detect the 384 SNPs. Results: The SNP genotypes rs3176343 C (P=0.02, OR=2.08, 95%CI, 1.14–3.78), rs468811 T (P=0.034, OR=2.01, 95%CI 1.04–3.88) were associated with HCC development in dominant model; and rs635551 C was associated with HCC development in codominant model (P=0.014, OR=2.45, 95% CI 1.17–5.11). The SNP genotypes rs468811 T was associated with non-LC HCC development in dominant model (P=0.018, OR=4.94, 95%CI 1.15–21.16); the rs4646425 T and rs2069522 T were associated with non-LC HCC development in codominant model (P=0.038, OR=2.01, 95%CI, 1.03–3.92; P=0.13, OR=2.46, 95%%CI, 1.19–5.08; respectively); the rs1057373 C was associated with non-LC HCC development in recessive model (P=0.010, OR=2.15, 95%CI 1.19–3.88). The rs17561 A and rs3176343 C were associated with LC-HCC development in dominant model (P=0.020, OR=1.86, 95%CI 1.09–3.15; P=0.03, OR=2.15, 95%CI, 1.06–4.33; respectively); the rs635551 C and rs10758326 T were associated with LC-HCC development in codominant model (P=0.043, OR=1.55, 95%CI 1.01–2.36; P=0.006, OR=2.85, 95%CI 1.13–6.50; respectively). Multivariate logistic regression analysis showed rs63551 (P=0.003, OR=3.52, 95%CI 1.54–8.06), rs3176343 (P=0.009, OR=2.38, 95%CI 1.24–4.56) and rs468811 (P=0.028, OR=2.24, 95%CI1.24–4.56) were associated with HCC development. Conclusion: These data suggested, in Chinese Han population, the SNPs rs3176343 C, rs468811 T and rs635551 C were the risk factors for HCC development; the SNPs rs468811 T, rs4646425 T, rs2069522 T and rs1057373 C were the risk factors for non-LC HCC development; the SNPs rs17561 A, rs3176343 C, rs635551 C and rs10758326 T were the risk factors for LC-HCC development.

Disclosures:

The following people have nothing to disclose: Zheng Zeng, Xian Liu

919

  1. Top of page

Prognosis predictors in patients with acute-on-chronic liver failure in chronic hepatitis B by hepatitis B virus flares

Jung Min Ha, Yong Han Paik, Geum Youn Gwak, Byung Chul Yoo;
Samsung Medical center, Seoul, Republic of Korea

Introduction: The prognosis of acute-on-chronic liver failure(ACLF) in chronic hepatitis B(CHB) is extremely poor. The patients are candidates of urgent liver transplantation(LT) for survival, while some patients recover by medical treatment such as antiviral therapy only. We investigated prognosis predictors including Model of end-stage liver disease (MELD) score. Method: We retrospectively reviewed 57 patients with ACLF in CHB by HBV flares from 2003 to 2012 at Samsung Medical Center, Seoul, Korea. ACLF was defined as hyperbilirubine-mia(Total bilirubin>5mg/dl), coagulopathy(Prothrombin time(INR)>1 .5) and complicated within 4 weeks by ascites and/or hepatic encephalopathy(HE). We checked HBV DNA titer, HBV serology and history of CHB diagnosis for inclusion and any coexistent cancer for exclusion. The patients were divided into two groups as outcome: 'Recovery group(RG)'(n= 35) consisted of patients recovered by medical treatment only (n=19) and undergone planned LT after 2 weeks later from admission date(n=16); 'Non-recovery group (NRG)' (n=22) consisted of patients died of liver failure progression(n= 14) and undergone emergent LT within 2 weeks after admission(n=8). We evaluated initial MELD score, serial MELD scores by 3 day interval for 5 times(on 1 st,4th,7th, 10th and 14th day) and other various clinical profiles. Result: In NRG, initial prothrombin time was more prolonged (2.79(1.64∼6.47) v.s 2.26(1.55∼4.65), p=0.012) and initial MELD score was higher than RG (31(21∼53) v.s 25(14∼36), p=0.003). While age, initial total bilirubin, AST, ALT, creatine and albumin level was not different significantly. There were larger proportion of cases with initial HE(>grade 3)(p=0.001), aggravated HE(>grade 3)(p=0.000, OR 8.46, CI 2.86∼40.08), systemic inflammatory response syndrome(p=0.000, OR 8.46, CI 2.45∼29.11), hepatorenal syndrome(HRS)(p=0.002) in NRG than RG. However ascites, varix bleeding, infection did not present significant distinction. By multivariate analysis, only initial HE,aggravated HE, HRS were significant independent predictors. The gap of MELD score with 1st day was significant on 14th day(2.6±5.6, p= 0.028) in RG and on 10th day (6±8.3, p=0.049) and 14th day(5.5±6.1, p=0.039) in NRG. There was significant increasing trend of MELD score over time in two groups (p= 0.001). The gradient of increase over time revealed smaller in RG than NRG, however this distinction was not significant.(p=0.121) Conclusion: We suggest that initial HE(>grade 3), aggravated HE and HRS imply progression of liver failure and need for urgent LT. Also we expect that initial MELD score and gradient of MELD score change over time may relate with prognosis.

Disclosures:

The following people have nothing to disclose: Jung Min Ha, Yong Han Paik, Geum Youn Gwak, Byung Chul Yoo

920

  1. Top of page

Characteristics of Hepatitis B Surface Antigen Clearance and HBsAb seroconversion in Korean Patients with HBeAg-negative Chronic Hepatitis B

Sung Wook Yang, Jung Wha Chung, Sang Soo Lee, Sukho Hong, Seong Min Chung, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong;
Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

Background : Hepatitis B surface antigen (HBsAg) seroclear-ance is a rare event in patients with chronic hepatitis B (CHB), and little is known about the pattern of HBsAb seroconversion in these patients. This study aimed to examine the characteristics and predictive factors of HBsAg loss / HBsAb seroconversion in HBeAg-negative chronic hepatitis B patients. Methods: Incidence of HBsAg clearance was retrospectively analyzed in HBeAg-negative CHB patients who visited our hospital. HBsAb seroconversion was examined in these patients, and clinical, biochemical and virologic correlations were made. Results : From Aug. 2003 to Oct. 2011, 1131 HBeAg(-) CHB patients visited hepatology outpatient clinic. Mean and median follow-up duration was 43.9 and 37.5 months, respectively. During follow-up, 20 patients showed loss of HBsAg. The cumulative incidence rates of HBsAg loss were 0.59, 1.44, 1.49 and 1.77% at 1, 3, 5, and 10 years. In these patients, cirrhosis was present in 7 patients, and four patients had history of antiviral therapy. Median serum HBV DNA level was 2000 copies/mL (0 - 314600 copies/mL), and mean transaminase levels were 38 and 50 for AST and ALT, respectively. Mean age was 55 years at the time of HBsAg loss, and mean follow-up duration until HBsAg clearance was 4.1 years (1.0–8.2 years, S.D. = 2.7 years). The duration till HBsAg loss was similar regardless of initial HBV DNA positivity. Clinical and virological parameters were not significantly different between patients with or without subsequent HBsAb seroconversion. Conclusions: HBsAg loss is a rare event in HBeAg-negative CHB patients in Korea with 0.17% annual loss rate which is lower compared to other Asian countries. Time to HBsAg clearance was variable and cannot be predicted by baseline clinical, biochemical or virological factors.

Disclosures:

The following people have nothing to disclose: Sung Wook Yang, Jung Wha Chung, Sang Soo Lee, Sukho Hong, Seong Min Chung, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong

921

  1. Top of page

Significant Fibrosis Among Patients with Chronic Hepatitis B Infection and Only Normal Serum Alanine Transaminase Levels: A Systematic Review and Meta-Analysis

David T. Chao2, Walid Ayoub1, Joseph K. Lim3, Long H. Nguyen4, Mindie H. Nguyen1;
1Division of Gastroenterology and Hepatol-ogy, Stanford University Medical Center, Palo Alto, CA; 2Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 3Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, CT; 4Stanford University School of Medicine, Stanford, CA

Background: Patients with chronic hepatitis B (CHB) with only normal ALT are presently not recommended for therapy. However, serum ALT alone may not be predictive of underlying hepatic fibrosis. The aim of this study is to determine the proportion of CHB patients with only normal ALT (< 40 IU/L) with significant fibrosis (stage > 2). Methods: Systematic PubMed search from 1/1990–6/2012 with associated bibliography and abstract selections from recent major scientific meetings was performed. Studies included were original studies with >30 treatment-naïve patients with >6 months follow-up. Study heterogeneity was assessed by visual inspection of forest plots and quantitatively using both the χ2-based Cochrane Q-statistic and I2 index statistic with p < 0.05 and I2 > 50% considered heterogeneous, respectively. Results: Nine studies with 830 patients met eligibility criteria and were included. Pooled estimate for significant fibrosis was 20.7% (95% CI16.2%-26.0%; p<0.0001). Visual inspection of the funnel plot did not yield appreciable publication bias. Similar significant rates of underlying fibrosis were noted when patients were sub-analyzed by HBeAg positivity (20.0%; 95% CI 8.9%-39.1%; p = 0.004; n=178), HBeAg negativity (18.2%; 95% CI 12.3%-26.2%; p<0.0001; n=550), HBV DNA > 10,000 copies/mL (20.3%; 95% CI 14.4%-27.7%; p<0.0001; n=294), and Asian ethnicity (20.5%; 95% CI 15.2%-27.0%; p<0.0001; n=547). Sub-analysis of reported data by revised ULN of ≦ 30 IU/L (males) and 19 IU/L (females) demonstrated significant fibrosis in 27.8% (95% CI, 19.0%-38.7%; p<0.0001; n=81). Conclusion: Approximately one-fifth of CHB patients with only ALT < 40 IU/L may have significant underlying fibrosis independent of HBeAg status, high HBV DNA levels, or Asian ethnicity. Approach to CHB patients with normal ALT should be individualized as further evaluation and possibly antiviral therapy may be appropriate in a subset of these patients.

Proportion of chronic hepatitis B patients with alanine aminotrans-ferase ≤ 40 IU/L and significant fibrosis stage > 2

Disclosures:

Joseph K. Lim - Consulting: Merck, Vertex, Gilead, Bristol Myers Squibb, Boehringer-Ingelheim; Grant/Research Support: Abbott, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Gilead, Janssen/Tibotec, Vertex, Achillion

Mindie H. Nguyen - Consulting: Gilead Sciences, Inc., Bristol-Myers Squibb, Bayer AG; Grant/Research Support: Gilead Sciences, Inc., Bristol-Myers Squibb, Novartis Pharmaceuticals, Roche Pharma AG

The following people have nothing to disclose: David T. Chao, Walid Ayoub, Long H. Nguyen

922

  1. Top of page

ALT Flares Are Infrequent During the Course of Pregnancy: Prospective Study from the Hepatitis B Research Network (HBRN) Adult Cohort Study

Natalie H. Bzowej1, Tram T. Tran5, Ruosha Li6, Steven H. Belle6, Coleman Smith3, Norah Terrault2, Mandana Khalili2, Naoky Tsai7, Daryl Lau4;
1Liver Transplant, Ochsner Medical Center, New Orleans, LA; 2University of California San Francisco, San Francisco, CA; 3University Of Minnesota, Minneapolis, MN; 4Harvard Medical School, Boston, MA; 5Cedars Sinai Medical Center, Los Angeles, CA; 6University of Pittsburgh, Pittsburgh, PA; 7Hawaii Medical Center, Honolulu, HI

Background: Studies of disease activity during pregnancy in chronic hepatitis b are few and limited to small retrospective case series. Therefore, it remains unclear how often to monitor patients during pregnancy. Aims: To prospectively investigate the serum ALT and hepatitis B virus (HBV) DNA levels during pregnancy and post-partum. Methods: Women enrolled into the NIDDK-funded HBRN adult cohort study, who were either pregnant when enrolled or became pregnant are included. Since treatment can affect natural history, data collected after the start of treatment are excluded. Pregnancy stages are defined as: pre-delivery <28 weeks and >28 weeks, and post-partum ≤16 weeks and >16 weeks. A disease flare is defined as serum ALT>200 U/L. The evolutions of ALT and log10 IU/mL HBV DNA levels over time were modeled by a mixed effect model. Pregnancy stage, HBeAg and their interaction were included as covariates. Results: From 1/1/2011 to 3/18/2013, 82 pregnant women with chronic HBV were enrolled or became pregnant after enrollment. There were 8 (10%) White, 11 (13%) Black, 62 (76%) Asian and 1 (1%) mixed/other. Characteristics when first known to be pregnant included: median age of 32 years (range 18–50 years), 43% of 70 with known status were HBeAg+ (medians: ALT 26 U/L, HBV DNA 8.3 log10 IU/mL) and 57% were HBeAg- (medians: ALT 24 U/L, HBV DNA 2.6 log10 IU/mL). There were 43 with pregnancy outcomes available: 39 live births, 3 miscarriages and 1 termination. Model estimates suggest ALT increases early post-delivery among both HBeAg+ and HBeAg- women (p<0.001), particularly among HBeAg+ women (see table). In contrast, DNA levels are relatively stable over time (NS for both HBeAg+ and HBeAg-women). Only 2 (2.4%) women had a flare. One pre-delivery >28 weeks, HBeAg- with peak ALT 225 U/L, the other <16 weeks post-delivery, HBeAg+ with peak ALT 205 U/L. Conclusion: Serum ALT levels increase post-delivery, particularly among HBeAg+ women with chronic HBV, but remain within normal range in most participants. Flares have been infrequent and mild thus far, and not associated with changes in HBV DNA levels or development of jaundice. On-going assessment in participants will help determine recommended monitoring guidelines for future participants.

Mixed model estimates of ALT (U/L)

Table 7. 
 HBeAs- HBe  
StageEstimate95<% CIEstimate95% CI
Pre-delivery <28 wks211725302436
>28 wks181423231830
Post-partum ≤16 wks3426439364136
>16 wks292336513869

Disclosures:

Natalie H. Bzowej - Advisory Committees or Review Panels: Vertex; Grant/Research Support: Genentech, Merck, Gilead Sciences, Vertex, Bristol Myer Squibb, Pharmasset; Speaking and Teaching: Gilead Sciences, Vertex

Tram T. Tran - Advisory Committees or Review Panels: Gilead, Bristol Myers Squibb, Vertex; Consulting: Gilead; Grant/Research Support: Bristol Myers Squibb; Speaking and Teaching: Bristol Myers Squibb, Gilead, Vertex

Steven H. Belle - Grant/Research Support: Rottapharm!Madaus

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

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

Naoky Tsai -Advisory Committees or Review Panels: Gilead, Vertex; Consulting: BMS, Gilead, Merck; Grant/Research Support: BMS, Gilead, Genentech, Vertex, Novartis, GSK, Bayer, Abbvie; Speaking and Teaching: BMS, Gilead, Genentech, Vertex, Merck, Salix, Bayer

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

The following people have nothing to disclose: Ruosha Li