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The Burden of Hepatitis C Infection in the 21st Century in the United States

Mina Kabiri, Alison Jazwinski, Andrew Schaefer, Jagpreet Chhatwal
University of Pittsburgh, Pittsburgh, PA

Purpose: Hepatitis C therapy is rapidly evolving and new antiviral agents are available that have substantially improved response rates. Newer agents in development are expected to further improve response rates, reduce side effects, and improve the uptake of treatment. Additionally, the CDC is currently recommending one time screening of all individuals born between 1945 and 1965. The aim of our study was to project the burden of hepatitis C virus infection in the United States in the 21st century by modeling the impact of the launch of new antiviral agents and implementation of birth-cohort screening. Methods: We developed a Markov simulation model that projected the prevalence and incidence of chronic HCV infection in the US. We defined the states by METAVIR fibrosis scores (F0-F4), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), liver transplantation (LT) and liver-related death. We simulated several treatment options starting from 2001 to 2020 including peginterferon-ribavirin, protease inhibitors, alloral regimens, and future “highly-effective” regimens based on published studies, data emerging from clinical trials, and expert opinion. We assigned sustained virologic response (SVR) rates by genotype, fibrosis score, treatment history, and interferonintolerance. We simulated the progression of HCV disease using data from previously published meta-analysis and clinical studies. Our model was calibrated and validated against data from CDC, NHANES-III and SEER. We also included one-time screening of people born during 1945-1965 with an increase in the annual HCV treatment capacity. Results: Our model projected that HCV will become a rare disease by 2040 with the implementation of new agents in the US. We estimated that the peak prevalence of DC will reach 64, 800 cases in 2017, and HCC cases will peak at 24, 000 cases in 2016. The number of deaths due to HCV is expected to reach the maximum of 19, 700 by 2018. With the implementation of birth-cohort screening, the number of cirrhotic patients, liver-related deaths and liver transplants is expected to decrease on average each year by 20. 4%, 6. 2% and 6. 7%, respectively in comparison with no screening. Conclusions: With the successful launch and implementation of new antiviral agents, HCV can become a rare disease by 2040. Treatment with future HCV therapies will significantly decrease the incidence of cirrhosis, HCC, liverrelated deaths and need for liver transplant. The number of cases of cirrhosis and HCC will reach their peak in the next 5 years and decrease afterwards. Birth-cohort screening with increased treatment capacity can further reduce the HCV disease burden.


Mina Kabiri - Grant/Research Support: This research was supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR000146.

Jagpreet Chhatwal - Consulting: Merck & Co., Inc.; Grant/Research Support: NIH/National Center for Advancing Translational Sciences

The following people have nothing to disclose: Alison Jazwinski, Andrew Schae-


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Successful Treatment with Sofosbuvir Regimen Improves Fatigue Scores in Patients with Chronic Hepatitis C (CHC)

Zobair M. Younossi1, 5, Maria Stepanova1, 5, Eric Lawitz2, David R. Nelson3, Kelly D. Kaita4, Fatema Nader1, Spencer Frost1, Sharon L. Hunt15
1Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA; 2Texas Liver Institute, Universify of Texas Health Science Center, San Antonio, TX; 3Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL; 4Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada; 5Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA

BACKGROUND: Fatigue is an important and debilitating symptom in patients with CH-C. Interferon-based treatment for CH-C worsens fatigue during treatment. AIM: Assess Fatigue in CH-C patients treated with Sofosbuvir (SOF) and ribavirin (RBV) with or without pegylated Interferon (PEG-IFN). METHODS: The fatigue-specific questionnaire, The Functional Assessment of Chronic Illness Therapy (FACIT-F), was administered at baseline, end-of-treatment and post-treatment to treatment-naīve G2 or 3 CH-C subjects receiving either SOF+RBV (N=201) for 16 weeks or 12-weeks followed up by 4 weeks of placebo (FUSION) and treatment-naϊve G1 CH-C subjects receiving PEG-IFN+RBV+SOF (N=327) for 12-weeks (NEUTRINO). Clinical-laboratory data were collected. Virologic data were blinded. RESULTS: Throughout the FUSION protocol, subjects randomized to 12-week vs. 16-weeks of SOF+RBV had similar FACIT-F scores (p>0. 05). Compared to their baselines, patients receiving SOF+RBV (FUSION) experienced more fatigue during treatment (a decline of 2. 89 in Fatigue scale, p=0. 025). Subjects receiving PEG-IFN+RBV+SOF (NEUTRINO) experienced even more substantial declines in their Fatigue scores (a decline of 10. 14 from baseline, p<0. 0001, and also p<0. 0001 compared to week 12 of SOF+RBV in FUSION). After 12 weeks of follow-up, significant improvement of fatigue was noted in patients who achieved SVR-12 in FUSION (N = 119, improvement in Fatigue scale score = +2. 97, p=0. 0036) or NEUTRINO (N=292, +2. 05, p=0. 0002). Multivariate analyses showed that depression (beta: −4. 4 to −7. 7, P<0. 05), female gender (beta: −3. 8 to −5. 3, p<0. 05) and clinical symptom of fatigue (beta: −6. 2 to −17. 3, p<0. 05) were the most important and consistent predictors of Fatigue scores at all time points in both studies. Liver cirrhosis was associated with worse fatigue in FUSION at baseline (beta = -4. 3, p=0. 016) but not at other time points during or after the end of treatment. CONCLUSIONS: Fatigue is worsened by PEG-IFN-related side effects and is less severely impacted by IFN-free regimens regardless of the length of active treatment. SVR-12 is associated with improvement in Fatigue scores.


Zobair M. Younossi - Advisory Committees or Review Panels: Merck, Vertex, Tibotec/J and J; Consulting: Gilead Sciences

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

Kelly D. Kaita - Advisory Committees or Review Panels: Gilead, Merck, Roche, Janssen, Boehringer, BMS, GSK, Vertex; Grant/Research Support: Gilead, Merck, Roche

The following people have nothing to disclose: Maria Stepanova, Fatema Nader, Spencer Frost, Sharon L. Hunt


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Industrial, not Fruit Fructose Intake is Associated with the Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C Patients

Salvatore Petta1, Gulio Marchesini2, Linda Caracausi1, Fabio S. Macaluso1, Calogero Comma1, Stefania Ciminnisi1, Daniela Cabibi3, Rossana Porcasi3, Antonio Craxi1, Vito Di Marco1
1Sezione di Gastroenterologia, DiBiMIS, University of Palermo, Italy, Palermo, Italy; 2Dipartimento di Scienze Mediche e Chirurgiche, “Alma Mater Studiorum, ” Universitá di Bologna, Italy, Bologna, Italy; 3Cattedra di Anotomio Patologica, University of Palermo, Italy, Palermo, Italy

Background and Aims: Unhealthy food intake, specifically fructose, has been associated to metabolic alterations and to the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C(G1 CHC), we tested the association of fructose intake with the severity of liver histology. Methods: Anthropometric and metabolic factors, including waist circumference(WC), waist-to-hip ratio(WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading(Scheuer classification), and graded for steatosis, which was considered moderate-severe if >20%. Features of nonalcoholic steatohepatitis(NASH) in CHC were also assessed(Bedossa classification). Results: Mean daily intake of total, industrial and fruit fructose was 18. 0 ± 8. 7 g, 6. 0 ± 4. 7 g, and 11. 9 ± 7. 2 g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR(p=0. 02) and hypercaloric diet(p<0. 001). CHC patients with severe liver fibrosis(>F3) reported a significantly higher intake of total(20. 8 ± 10. 2 vs. 17. 2 ± 8. 1 g/day; p=0. 04) and industrial fructose(7. 8 ± 6. 0 vs. 5. 5 ± 4. 2; p=0. 01), not fruit fructose(12. 9 ± vs. 11. 6 ± 7. 0; p=0. 34). Multivariate logistic regression analysis showed that older age(OR 1. 051, 95%CI 1. 007- p=0. 02), severe necroinflammatory activity(OR 3. 261, 95%CI 1. 310-8. 120, p=0. 01), moderate-severe steatosis(OR 2. 430, 95%CI 1. 018-6. 426, p=0. 04), and industrial fructose intake(OR 1. 147, 95%CI 1. 046-1. 257, p= 0. 003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH. Conclusions: The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1CHC.


Giulio Marchesini - Advisory Committees or Review Panels: Sanofi-Synthelabo; Grant/Research Support: Merck Sharp & Dome; Speaking and Teaching: Novo Nordisk, Merck Sharp & Dome, Boerhinger Ingelheim, Lilly

The following people have nothing to disclose: Salvatore Petta, Linda Caracausi, Fabio S. Macaluso, Calogero Cammá, Stefania Ciminnisi, Daniela Cabibi, Rossana Porcasi, Antonio Craxi, Vito Di Marco


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Declining HCV Treatment Rate in the USA

Sarah Brown1, Victoria Allan1, Christopher E. Smith2, Raquel Nunez1
1Ipsos Healthcare, London, United Kingdom; 2lpsos Healthcare, New York, NY

OBJECTIVES The objective of this paper is to discuss the treatment rate of HCV patients under care, in light of new product launches expected in 2013/14. METHODOLOGY Ipsos Healthcare's HCV Therapy Monitor study reviews patient record data from a representative sample of HCV-treating physicians in the USA on a quarterly basis. Participating physicians provide information on their next 10 HCV patients seen within the corresponding quarter. This analysis includes data from Q2 2011 一 Q1 2013. RESULTS Tracking treatment rates prior to the launch of two HCV protease inhibitors (boceprevir and telaprevir) in September 2011 through to present day shows clear trends. In Q2 2011, pre PI launch, only 16% of Genotype 1(G1) patients were on treatment. Following the availability of these products, this treatment rate doubled to 27% in Q4 2011. Since the peak that immediately followed the PI launch, there has been a constant decline in G1 patients on treatment; in Q1 2013 this figure was just 19%. This decline is predicted to continue up until the launch of new treatment options for G1 patients, expected Q4 2013/Q1 2014. The decrease in patients on treatment is coupled with more selective treatment criteria. The proportion of treated G1 patients with no/minimal liver damage has decreased from 45% to 26%, signifying that only the more advanced patients are now being treated. Alongside the decline in treatment rate, physicians have stated a corresponding increase in patients amongst the untreated patient pool waiting for better treatments. In Q1 201 3, 48% of untreated G1 patients were waiting for better treatments, compared to just 24% immediately post PI launch. Treatment rates have been consistently higher in G2/3 patients than in G1 patients in the USA. However, in anticipation of the first new treatment options expected for this patient group since 2001, treatment rates are declining. The proportion of treated G2/3 patients has decreased from 43% in Q2 2011 to 29% in Q1 2013. Similar to G1 patients, the proportion of untreated G2/3 patients for whom a physician has indicated the desire to wait for better treatments has increased from 22% in Q4 2011 to 43% currently. CONCLUSIONS It is evident that for those patients who can afford to wait, physicians are delaying treatment in anticipation of new product launches. Patients with no/minimal liver damage who can wait for treatments with increased efficacy/better tolerability/more convenient dosing are being advised to do so.


Sarah Brown - Employment: Ipsos Healthcare Christopher E. Smith - Employment: Ipsos Healthcare

The following people have nothing to disclose: Victoria Allan, Raquel Nunez


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HCV Genotype and risk of Cirrhosis and Hepatocellular Cancer in a National Sample of Veterans with HCV

Jawad Ilyas1, 2, Jennifer R. Kramer1, 2, Hashem El-Serag1, 2, Zhigang Duan1, 2, Gia L. Tyson1, 2, Fasiha Kanwal1, 2
1Gastroenterology Baylor College of Medicine, Houston, TX; 2Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX

Background: There is some evidence that HCV viral genotype may be associated with the risk of cirrhosis and hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. However, previous studies have been too small to provide convincing data regarding the effect of HCV genotype on cirrhosis and HCC risk after accounting for demographic, clinical, and birth cohort factors. Methods: We identified patients with active HCV infection, confirmed by positive PCR and a known HCV genotype, from the VA HCV Clinical Case Registry between 1995 and 2010. We examined only patients with at least two years of follow-up time. We defined cirrhosis and HCC based on the earliest recorded validated ICD9 codes through the end of 2010. We performed Cox proportional hazards analyses to examine the effect of HCV genotype on time to cirrhosis and HCC adjusting for patients' age, period of service (World War I/II, Vietnam era, post-Vietnam era), race, gender, HIV infection, HBV infection, alcohol use, diabetes, body mass index, and antiviral treatment receipt. We conducted 2 sensitivity analyses using an alternative definition of cirrhosis as an outcome (ICD9 codes in combination with AST to platelet ratio > 2) and using year of birth in lieu of patients' age to adjust for birth cohort effect. Results: There were 107, 152 patients with active HCV viremia. Of these, 85, 498 (79%) had HCV genotype 1, 12, 798 (12%) genotype 2, 7798 (7. 3%) genotype 3, and 1058 (1%) had HCV genotype 4 infection. Patients with HCV genotype 2 or 3 were significantly more likely to be Caucasian or non Hispanic white (65% and 69% vs. 43%) and less likely to be diabetic (10. 3% and 7. 8% vs. 12. 6%) than patients with HCV genotype 1. Patients with genotype 3 were also younger than genotype 1 and 2 patients (mean age 49. 1 vs. 51. 5 yr). The risk of cirrhosis and HCC varied significantly by viral genotype. Compared to patients with HCV genotype 1, those with genotype 2 had a lower risk of cirrhosis (unadjusted hazard ratio, HR=0. 78, 95% CI=0. 73-0. 84) and HCC (HR=0. 64, 95% CI=0. 56-0. 75). In contrast, patients with genotype 3 had a higher risk of developing cirrhosis (HR = 1. 38, 95% CI = 1. 31-1. 46) and HCC (HR=1. 53, 95% CI=1. 35-1. 73) than HCV genotype 1. Adjusting for pre-specified variables, replacing age with birth year and using alternative definition of cirrhosis did not change the direction or magnitude of these associations. Conclusions: HCV genotype is strongly associated with the risk of developing cirrhosis and HCC. This association is independent of patients' age or year of birth and persisted after adjusting for a range of factors including diabetes and BMI.


Hashem El-Serag - Consulting: Gilead

The following people have nothing to disclose: Jawad Ilyas, Jennifer R. Kramer, Zhigang Duan, Gia L. Tyson, Fasiha Kanwal


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Minimal Impact of Sofosbuvir+Ribavirin (SOF+RBV) on Work Productivity of Patients with Chronic Hepatitis C (CH-C)

Zobair M. Younossi1,5, Maria Stepanova1,5,Eric Lawitz2, David R. Nelson3, Curtis Cooper4, Fatema Nader1, Mariam Afendy1, Sharon L. Hunt1,5
1Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA; 2Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 3Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health Science Center, San Antonio, TX; 4Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada; 5Betty and Guy Beatty Center for Integrated Research, Inova Health System' Fails Church, VA

BACKGROUND: Interferon-based treatment for CH-C causes substantial side effects which negatively impact activity and work productivity. Interferon-free treatment regimens are currently being developed. AIM: To assess work productivity of CH-C patients treated with SOF+RBV with or without pegylated Interferon (PEG-IFN). METHODS: The Work Productivity and Activity Index: Specific Health Problem (WPAI: SHP) is a validated tool for evaluation of impairment in work productivity (includes both absenteeism from work and lower productivity while working) and daily activities as a result of a given health problem. Referring to HCV infection of the study participants, WPAI: SHP was administered at baseline, end-of-treatment and post-treatment to previously untreated G2 or 3 CH-C subjects receiving either SOF+RBV (N=201) for 12-weeks or 16 weeks (FUSION) and treatment-naīve gi CH-C subjects receiving PEG-IFN+RBV+SOF (N=327) for 12-weeks (NEUTRINO). Clinical-laboratory data were collected. Virologic data were blinded. RESULTS: At baseline, during treatment and at the endof-treatment, subjects receiving 12-week vs. 16-weeks of SOF+RBV (FUSION) had similar WPAI scores (p>0. 05). During treatment, patients receiving PEG-IFN-RBV+SOF had significantly more impairment as indicated by both activity and work productivity scores [FUSION: an impairment of 0. 25 in activity and 0. 21 in work productivity; both p<0. 01 compared to baseline; NEUTRINO: impairment of 0. 38 in activity and 0. 30 in work productivity; both p<0. 0001 compared to baseline; (WPAI scale: 0-1 where 1 indicates 100% impairment). At the end of follow-up, both groups returned to their baseline work status. Furthermore, at the end of follow-up, patients achieving SVR in NEUTRINO showed improvement in their activity score compared to their baseline (p=0. 0367) and tended to show improvement in work productivity score (p=0. 052). In multivariate analysis, baseline depression and fatigue were the most consistent predictors of impairment in work productivity at all time points (for depression, beta=0. 102 to 0. 166; for fatigue, beta=0. 093 to 0. 271, all p<0. 05). CONCLUSIONS: Work productivity is negatively impacted by PEG-IFN related side effects. SVR is associated with some improvement in activity. Although achieving SVR may be associated with improved work productivity and activity, the levels only borderline exceed the baseline by post-treatment week 12. Additional follow up is needed to appreciate the long term impact of SVR on these assessments.


Zobair M. Younossi - Advisory Committees or Review Panels: Merck, Vertex, Tibotec/J and J; Consulting: Gilead Sciences

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche, MERCK

The following people have nothing to disclose: Maria Stepanova, Fatema Nader, Mariam Afendy, Sharon L. Hunt


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Antiretroviral medications, lipodystrophy and cirrhosis in HIV-infected patients

George N. Ioannou1 ,2, Christopher Bryson1,2, Noel S. Weiss3, Edward J. Boyko1, 2
1Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA; 2Medicine, University of Washington, Seattle, WA; 3Epidemiology, University of Washington, Seattle, WA

Background and Aims Many HIV antiretroviral medications have been associated with chronic liver injury. HIV and highly active antiretroviral treatment (HAART)-Associated Lipodystrophy Syndrome (HALs) is frequently characterized by accumulation of intra-abdominal fat, insulin resistance and hepatic steatosis. We sought to determine whether long-term exposure to specific antiretroviral medications or the presence of HALS predispose HIV-infected patients to the development of cirrhosis. Methods HIV-infected patients with cirrhosis who received care in the Veterans Affairs healthcare system nationally in 2009 were matched by HCV co-infection status and year of first visit for HIV in the VA to HIV-infected patients without cirrhosis in a 1: 3 ratio. Results Among HIV/HCV co-infected patients (593 with cirrhosis and 1591 matched controls), HALS was associated with a significantly increased risk of cirrhosis (adjusted odds ratio (AOR) 1. 6, 95% CI 1. 1-2. 3) especially among Black patients (AOR 2. 9, 95% CI 1. 6-5. 2). Also, among HIV/HCV co-infected patients, longer cumulative exposure to all antiretroviral medications, all NRTIs, all Pis and selected individual medications (didanosine, stavudine and nelfinavir) were significantly associated with cirrhosis. In contrast, among HIVinfected patients not co-infected with HCV (245 with cirrhosis and 658 matched controls), HALS or exposure to antiretroviral medications were not significantly associated with cirrhosis, with the exception of didanosine. Conclusions HALS and cumulative exposure to all antiretroviral medications, especially stavudine, didanosine and nelfinavir, were associated with the development of cirrhosis in HIV/HCV co-infected patients, but not in HIV monoinfected patients.

Association between lipodystrophy and development of cirrhosis in HIV-infected patients

No Cirrhosis N=658Cirrhosis N=255Age-Adjusted Odds Ratio for CirrhosisMultivariated Adjusted* Odds Ratio for CirrhosisNo Cirrhosis N=1591Cirrhosis N=593Age-Adjusted Odds Ratio for CirrhosisMultivariate Adjusted* Odds Ratio for Cirrhosis
  1. * Adjusted by multivariate conditional logistic regression for age, gender, diabetes, body mass index, race, ethnicity, history of alcohol abuse or dependence, history of drug abuse or dependence, response to HCV antiviral treatment (for HCV-positive patients only), cumulative exposure to antiretroviral medications and lipodystrophy.

All Patients
Lipodystrophy9. 6%11. 8%1. 1(0. 7-1. 8)1. 4 (0. 8-2. 5)5. 0%10. 1%2. 0(1. 4-2. 8)1. 6 (1. 1-2. 3)
White Patients
Lipodystrophy13. 0%15. 7%1. 1(0. 6-2. 0)1. 6 (0. 8-3. 2)9. 2%12. 6%1. 3 (0. 8-2. 2)1. 4 (0. 8-2. 4)
Black Patients
Lipodystrophy4. 7%4. 8%0. 9 (0. 3-2. 9)1. 3 (0. 4-4. 4)2. 6%8. 8%3. 4(1. 9-6. 0)2. 9 (1. 6-5. 2)


The following people have nothing to disclose: George N. Ioannou, Christopher Bryson, Noel S. Weiss, Edward J. Boyko


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KLF12 polymorphism improves ITPA predictability of anemia in hepatitis C treated with peginterferon+ribavirin

Javier Ampuero1, Jose A. Del Campo1, Lourdes Rojas1, Lourdes Ortiz-Fernandez2, Angela Rojas1, Marta Conde2, Marta GarcίaValdecasas1, José-RaỦl Garcίa-Lozano2, Ricard Solá3, Xavier Forns4, Ricardo Moreno-Otero5, Raul J. Andrade6, Moises Diago7, Javier Salmeron8, Luis Rodrigo9, Jose A Pons10, J. M. Navarro11, Jose Luis Caleja12, Javier Garcίa-Samaniego13, Maria Buti14, Raquel Millan1, Marίa F. González-Escribano2, Manuel RomeroGomez1
1Unit for Clinical Management of Digestive Diseases, Valme University Hospital, Sevilla, Spain; 2Immunology Unit, Virgen del Rocio Hospital, Sevilla, Spain; 3Hepatology Unit, Mar Hospital, Barcelona, Spain; 4Liver Unit and ciberehd, Clinic Hospital. IDIBAPS, Barcelona, Spain; 5Hepatology Unit and ciberehd, Princesa Hospital, Madrid, Spain; 6Digestive Unit and ciberehd, Virgen de la Victoria University Hospital, Malaga, Spain; 7Digestive Department, General Hospital, Valencia, Spain; 8Digestive Unit and ciberehd, San Cecilio University Hospital, Granada, Spain; 9Digestive Department, Asturias Hospital, Oviedo, Spain; 10Digestive Department, Virgen de la Arrixaca University Hospital, Murcia, Spain; 11Digestive Department, Costa del Sol Hospital, Marbella, Spain; 12Digestive Department, Puerta de Hierro Hospital, Madrid, Spain; 13Digestive Unit and ciberehd, Carlos III Hospital, Madrid, Spain; 14Hepatology Unit and ciberehd, Vall d'hebron Hospital, Barcelona, Spain

Background and aim: Inosine triphosphate pyrophosphatase (ITPA) and Kruppel-like factor 12 (KLF12) have been identified as genetic factor associated with protection from hemolytic anemia induced by ribavirin. We assessed the interaction between KLF12 and ITPA polymorphisms together with environmental factors on anemia in patients with chronic hepatitis C receiving peginterferon and ribavirin (P+R). Methods: Blood from 1, 080 patients with hepatitis C, treated with P+R during 24-48 weeks according to viral genotype, was collected. Anemia was defined as hemoglobin (Hb) < 10g/dL at week 4, 12 or 24. SNPs ITPA1: rs1127354; ITPA2: rs7270101; and KLF12: rs9543524 were studied by Taqman probe (Applied Byosistems, Barcelona, Spain). Univariate analysis was made using the Mann-Whitney U test, the Student t-test or ANOVA for continuous variables, and the Chi-square or the Fisher exact probability test for categorical data. Logistic regression was used in multivariate analysis. Results: Anemia was present in 22. 6% of patients (244/1, 080). G allele of KLF12 was present in 34. 8%; A allele of ITPA1 in 11. 1%; and C allele of ITPA2 in 23. 1%. In the overall cohort, KLF12-G showed protection from anemia (17. 9% vs 29. 6%; p=0. 002), as well as ITPA2-C (15. 4% vs 24. 8%; p=0. 006) but not ITPA1 (16. 9% vs 23. 9%; p=0. 15). In ITPA2-non-A patients bearing KLF12-G showed lower anemia rate (16. 3% vs 34. 1%; p=0. 0001). In multivariate analysis, independent variables associated with anemia were: age [Or 1. 04 (IC95% 1. 01-1. 06); p=0. 001], baseline Hb [OR 0. 65 (IC95% 0. 55-0. 77); p=0. 0001], KLF12-G [OR 0. 45 (IC95% 0. 27-0. 74); p=0. 002] and ITPA2-C [OR 0. 43 (IC95% 0. 24-0. 77); p=0. 005]. Similar results were obtained in multivariate analysis in HCV-1 genotype. In non-1 genotype, KLF12-G showed protection from anemia (8. 3% vs 29%; p=0. 002), but not ITPA1-A (17. 4% vs 20. 3%; p=0. 740) and ITPA2-C (12. 3% vs 21. 8%; p=0. 119). Multivariate analysis showed baseline Hb [OR 0. 44 (IC95% 0. 30-0. 64); p=0. 0001] and KLF12-G [OR 0. 20 (IC95% 0. 06-0. 69); p=0. 011] as independently variables associated with anemia in non-1 genotype patients. Diagnosis accuracy for anemia prediction was 0. 82 (IC95% 0. 73-0. 89; p=0. 0001) in genotype non-1 patients. Conclusion: Presence of allele G in KLF12, allele C in ITPA-2 and younger age with higher baseline Hb seem to protected from anemia. KLF12-G but not ITPA-2 together with baseline Hb accurately predicts anemia in non-1 genotype patients. Therefore, KLF12 alone or in combination with ITPA polymorphisms could be an accurate strategy to predict risk of anemia.


Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Moises Diago - Grant/Research Support: BOHERINGER, ROCHE, MSD, GILEAD, BMS, GSK, JANSEN, ABBVIE

Javier Garcia-Samaniego - Consulting: Boehringer-Ingelheim

Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

Manuel Romero-Gomez - Advisory Committees or Review Panels: Roche Farma, SA., MSD, S. A., Janssen, S. A., Abbott, S. A.; Grant/Research Support: Ferrer, S. A.

The following people have nothing to disclose: Javier Ampuero, Jose A. Del Campo, Lourdes Rojas, Lourdes Ortiz-Fernandez, Angela Rojas, Marta Conde, Marta Garcίa-Valdecasas, José-RaỦl Garcίa-Lozano, Ricard Sola, Ricardo Moreno-Otero, Raul J. Andrade, Javier Salmeron, Luis Rodrigo, Jose A Pons, J. M. Navarro, Jose Luis Calleja, Raquel Millán, Marίa F. González-Escribano


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IL28B Influences Racial/Ethnic Differences in LiverRelated Mortality Among HIV/HCV Co-Infected Women

Monika Sarkar1, 3, Mark H. Kuniholm2, Eric Vittinghoff3, Audrey French4, Howard Minkoff5, Michael Plankey6, Bradley E. Aouizerat7, Marion G. Peters1
1Medicine, University of California, San Francisco, San Francisco, CA; 2Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY; 3Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA; 4Medicine, Stroger (Cook County) Hospirnl, Chicago, IL; 5Obstetrics and Gynecology, SUNY Downstate Medical Center, Brooklyn, NY; 6Medicine, Georgetown University Medical Center, Washington, DC; 7Nursing, University of California, San Francisco, San Francisco, CA

We have previously shown that African American HIV/HCV coinfected women have lower liver-related mortality compared to Caucasians and Hispanics. IL28B single nucleotide polymorphisms (SNPs) may be associated with differential rates of fibrosis between racial/ethnic groups, although its ultimate contribution to liver-related death is unknown. In a large cohort of HIV/HCV co-infected women, we assessed the contribution of IL28B SNPs to known racial/ethnic differences in liver-related mortality. We conducted a retrospective cohort study of HIV/HCV co-infected women followed in the multi-center Women's Interagency HIV Study (WIHS). The eligible cohort (n=794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. Data on HIV immune status, HCV-related factors, co-morbid conditions, and nine available IL28B SNPs were collected. Cox proportional hazards models were used to assess overall and liver-related mortality. Competing risks analyses and tests for interaction between IL28B SNPs and race/ethnicity were performed. Women were followed for up to 18 years (median follow-up 9. 2 years) with 471 deaths and 55 liver-related deaths. Among Caucasians, Hispanics, and African Americans, 18%, 17%, and 22%, respectively, had the GG genotype of rs12980275, while 23%, 20%, and 27% had the TT genotype of rs12979860. Of nine studied IL28B SNPs, only the GG genotype of rs12980275 and TT genotype of rs1297986 were associated with lower risk of liver-related death. African American women had significantly lower liverrelated death compared to Caucasians and Hispanics, independent of these IL28B polymorphisms (Table 1). There were no differential effects of race/ethnicity or IL28B on all-cause mortality (p values > 0. 1). Conclusions: In the first study to link IL28B and liver-related mortality, we identified a lower risk of death associated with IL28B SNPs in a large cohort of HIV/HCV co-infected women. Though IL28B appears to impact death from hepatitis C, additional genomic studies within the WIHS may further elucidate the reasons for the marked and persistent racial/ethnic discrepancy in liver-related mortality among co-infected women.

Table 1. Contribution of IL28B SNPs to Racial/Ethnic Differences in Liver-Related Death

PredictorAge Adjusted HR (95% CI)p-valueMultivariate (MV)* Model HR (95% CI)p-valueMV Model + Race/Ethnicity HR (95% CI)p-valueMV Model rs 12979860 HR (95% CI)p-valueMV Model rsl 2980275 HR (95% CI)p-value
  1. *Multivariate Model - Adjusted for Age, CD4 count, HIV viral load, HCV viral load

rs12980275 GG vs AA0. 3 (0. I-0. 9)0. 030. 3 (0. 1-0. 9)0. 030. 4 (0. 1-1. 1)0. 07
rs 12979860 TTvsCC0. 5 (0. 2-1. 1)0. 070. 5 (0. 2-1. 1)0. 080. 6 (0. 3-1. 4)0. 3
African American vs Caucasian0. 5 (0. 3-1. 1)0. 090. 4 (0. 2-0. 9)0. 02 0. 5 (0. 2-0. 95)0. 040. 5 (0. 2-0. 95)0. 04
African American vs Hispanic0. 4 (0. 2-0. 7)0. 0030. 3 (0. 2-0. 6)0. 001 0. 3 (0. 2-0. 6)0. 0010. 3 (0. 2-0. 6)0. 001


Marion G. Peters - Advisory Committees or Review Panels: Theravance, Clinical Care Options, International Antiviral Society, Janssen; Consulting: Genentech, Roche, Merck; Employment: Hoffman La Roche -Spouse

The following people have nothing to disclose: Monika Sarkar, Mark H. Kuniholm, Eric Vittinghoff, Audrey French, Howard Minkoff, Michael Plankey, Bradley E. Aouizerat


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Dietary cholesterol intake is associated with death and liver transplantation in chronic hepatitis C virus infection: Analysis of extended follow-up data from the HALT-C trial

Lei Yu1, Chihiro Morishima3, George N. Ioannou 1, 2
1Medicine, University of Washington, Seattle, WA; 2Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA; 3Lab Medicine, University of Washington, Seattle, WA

Background and Aim: We aimed to determine whether dietary cholesterol intake is associated with mortality in patients with chronic hepatitis C virus (HCV) infection. Methods: Using extended follow-up data from the Hepatitis C Antiviral Longterm Treatment against Cirrhosis (HALT-C) Trial, which included patients with advanced fibrosis and compensated cirrhosis, we investigated whether cholesterol intake among 630 participants who completed Food Frequency Questionnaires at baseline and 1. 8 years later was associated with death or liver transplantation. Results: After an average follow-up of 4. 8 years, 68 patients died from any cause and 43 patients underwent liver transplantation with an incidence rate of 36. 8 per 1, 000 person-years. After adjustments for potential confounders, each higher quartile of cholesterol intake was associated with an 82% increase in the risk of death or transplantation (adjusted hazard ratio [AHR] 1. 82, 95% CI 1. 36-2. 45, P-value for trend<0. 001). Compared to patients in the lowest quartile of cholesterol intake (32-151 mg/day), patients in the 3rd (220308 mg /day, AHR 3. 01, 95% CI 1. 47-6. 15) and 4th quartile (>308 mg/day, AHR 5. 85, 95% CI 2. 32-14. 7) had significantly increased risk of death or transplantation (Table). The risks were similar for liver-related deaths or transplantation (AHR 1. 64, 95% CI 1. 15-2. 33, P-value for trend=0. 006). Conclusion: Higher dietary cholesterol intake was associated with increased risk of death and liver transplantation in HCV infected patients with advanced fibrosis or compensated cirrhosis.

Milligrams cholesterol IntakeNPerson-yearsDeath or transplantIncidence (per 1, 000 person-years)AHRa (95% CI)AHRb (95% CI)P-value for trend b
32-1511587902329. 111
152-2201577362432. 61. 66 (0. 90-3. 05)1. 49 (0. 75-2. 97)
220-3081587222940. 12. 34 (1. 27-4. 32)3. 01 (1. 47-6. 15)
>3081577643545. 84. 65 (2. 15-10. 0)5. 85 (2. 32-14. 7)<0. 001, AHR 1. 82 (1. 36-2. 45)


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Incremental Costs and Healthcare Resource Utilization Associated with Advanced Liver Disease among Commercially-Insured Patients with Chronic Hepatitis C Virus

Jillian G. Scaife1, Effie Kuti2, Fotios K. Kokkotos1, Gavin S. Miyasato1, Joseph K. Lim3, Zheng Wang1, Daina S. Anhalt1, Stephen Sander2, Herman Sanchez1
1Trinity Partners, Waltham, MA; 2Health Economics and Outcomes Research, Boehringer Ingelheim, Inc. Ridgefield, CT; 3Yale University School of Medicine, New Haven, CT

PURPOSE: The objective was to determine the incremental cost and healthcare resource utilization (HCRU) associated with diagnosed chronic HCV patients who have developed advanced liver disease (AdvLD) 一 decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), or liver transplant 一 relative to diagnosed chronic HCV patients without AdvLD. METHODS: This study was based on 2007-2011 administrative claims from a large, nationwide database of commerciallyinsured patients. ICD-9 and CPT codes were used to identify patients that were diagnosed with HCV and AdvLD. Four chronic HCV patient cohorts were evaluated 一1) those with DC, 2) those with HCC, 3) those that received a liver transplant, and 4) those without AdvLD, which served as a common comparator group to each HCV AdvLD cohort. Annualized all-cause reimbursed medical service costs (includes inpatient, outpatient, emergency room and physician office medical services but excludes pharmacy costs) and hospitalizations were then modeled for each HCV AdvLD cohort and compared to the HCV non-AdvLD reference cohort. Costs and HCRU were estimated using a generalized linear model fitted with a gamma distribution and log link function. To adjust for differences in baseline patient profiles, the models included covariates based on propensity scores, derived using logistic regression on demographics and comorbidities. RESULTS: Relative to chronic HCV patients without AdvLD, the overall annual incremental cost of chronic HCV patients with DC was $31, 701 (point estimate and 95% bounds were $42, 716±$882 versus $11, 016±$83). Similarly, chronic HCV patients with HCC were more costly relative to those without AdvLD (incremental cost: $93, 353, $104, 596±$12, 963 versus $11, 243±$234). The incremental annual cost of chronic HCV patients who had had a liver transplant was $203, 326 ($214, 737±$29, 092 versus $11, 411+$233). All incremental costs had p-values < 0. 0001. Furthermore, chronic HCV patients with AdvLD were hospitalized more than those without AdvLD: DC (2. 78±0. 03 versus 1. 19±0. 01), HCC (3. 28±0. 08 versus 1. 19±0. 01) and liver transplant (2. 69±0. 09 versus 1. 19±0. 01). All differences were statistically significant with p < 0. 0001. CONCLUSIONS: Evaluation of commercial claims data indicates that patients diagnosed with chronic HCV and AdvLD have higher HCRU and hospitalization rates than diagnosed chronic HCV patients without AdvLD. As the severity of the AdvLD progresses, the overall healthcare costs and HCRU increase. In context of current literature this study highlights the real-world expenditure associated with different stages of AdvLD among HCV patients by examining the recent commercial claims data.


Gavin S. Miyasato - Employment: Trinity Partners

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

Stephen Sander - Employment: Boehringer Ingelheim Pharmaceuticals, Inc.

The following people have nothing to disclose: Jillian G. Scaife, Effie Kuti, Fotios K. Kokkotos, Zheng Wang, Daina S. Anhalt, Herman Sanchez


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IL28B genotype distribution using a non-invasive test: Impact on treatment decision in 1007 naϊve and experienced-patients with genotype 1 and 4 chronic hepatitis C in real life clinical practice: A prospective multicenter cohort

Philippe Halfon1, 2, Denis Ouzan3, Tarik Asselah4, Christophe Renou5, Thierry Allegre6, Patrick Delasalle7, Alain Lafeuillade8, Jean francois D. Cadranel9, Nabil Haddad10, Guillaume Penaranda1, Hacéne Khiri1, Marc Bourliére11
1Laboratoire ALPHABIO, Marseille, France; 2Hôpital Ambroise-Paré, Marseille, France; 3Institut Arnault Tzanck, Saint Laurent du Var, France; 4Hôpital Beaujon, Clichy, France; 5Hôpital d'Hyéres, Hyéres, France; 6Hôpital du Pays d'Aix, Aix en Provence, France; 7Clinique du Palais, Grasse, France; 8Hôpital Saint-Musse, Toulon, France; 9Hôpital Laennec, Creil, France; 10Cabinet Médical, MaisonsAlfort, France; 11 Hôpital Saint-Joseph, Marseille, France

Background: IL28B genotype has been shown to be the strongest pretreatment predictor of sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C infection (CHC) treated with pegylated interferon (peg-IFN) and ribavirin (RBV). However, IL28B genotype impact on treatment decision in real life practice is unknown. Objective: To prospectively analyze IL28B genotypes distribution upon 1007 HCV genotype 1(G1) or 4 (G4) infected patients with or without HIV co-infection, using a validated buccal epithelial cells samples in real life clinical practices (Halfon P et al. Plos One 2012). Patients & Methods: From October 2011 to March 2013, 1007 CHC patients were included among 127 French clinical centers: there were 601(60%) males; mean age 53 ± 19 years old; there were 856 (85%) HCV genotype 1, and 126 (13%) HCV genotype 4; 526 (52%) were treatment naives; 592 (59%) had significant fibrosis (>F2); 112 (11%) were HIV-HCV co-infected; 358 (36%) were actual or former drug users; and 227 (23%) were actual or former alcohol consumers. Among the 127 investigators, 73 (57%) were from private office based, 34 (27%) from general hospitals, and 20 (16%) from university hospitals. Results: Il28B CC, CT, and TT genotypes distribution was 252 (25%), 576 (57%), and 177 (18%) respectively. In the 856 HCV G1 patients IL28B distribution was CC 216 (25%), CT 494 (58%), and TT 146 (17%). In the 126 HCV G4 patients, IL28B distribution was CC 32 (25%), CT 69 (55%), and TT 25 (20%). Treatment decisions were recorded and matched with initial intentions on 433 patients. In the intention to treat group, there were less HCV G4 (7% versus 13%, p=0. 03), more F3/4 (43% versus 28%, p=0. 004), less coinfected patients (10% versus 25%, p<. 0061). In the intention not to treat group, treated patients were more likely IL28B CC compared with untreated patients (32% vs. 17%, p=0. 02), and were more often treated in liberal settings (68% vs. 35%, p=0. 001). Conclusion: This prospective multicenter study is a large study conducted assessing the distribution of IL28B in real-life clinical practice. Regarding reliability of the IL28B endobuccal sampling, this process has to be considered in future prospective IL28B assessment due to its easy-to-use and high acceptability by the patient. Our study showed that IL28B is used for the management of HCV infected patients. In the context of future treatments; IL28B genotyping may remain useful if it can be used to individualize treatment strategies, identifying patients who can be successfully treated with shorter, simpler, or cheaper regimens.


Philippe Halfon - Consulting: roche; Management Position: genoscience; Speaking and Teaching: merck, janssen; Stock Shareholder: alphabio

Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen


Marc Bourliere - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghel mein, Merck, Schering-Plough, Bohringer inghelmein, Merck; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

The following people have nothing to disclose: Denis Ouzan, Christophe Renou, Thierry Allegre, Alain Lafeuillade, Jean francois D. Cadranel, Nabil Haddad, Guillaume Penaranda, Hacene Khiri


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Genome wide association study of hepatitis C virus- and cryoglobulin-related vasculitis

Anna Linda Zignego2, Genevieve L. Wojcik1, Patrice Cacoub3, Marcella Visenfini4, Massimo Fiorilli4, Benjamin Terrier3, Alessandra Mongio5, Rachel Latanich1, Edgar Charles6, Salim I. Khakoo7, Michael P. Busch8, Lynn B. Dustin6, David L. Thomas1, Priya Duggal1
1Department of Medicine, Johns Hopkins Medical Insfifufion, Baltimore, MD; 2Universify of Florence, Florence, Italy; 3Piette-andMarie-Currie University, Paris, France; 4University of Rome, Rome, Italy; 5Casa Sollievo della Soffrenza Hospital, San Giovanni Rotondo, Italy; 6Rockefeller University, New York City, NY; 7University of Southampton, England, Southampton, United Kingdom; 8Blood Systems Research Institute, San Francisco, CA

Background: Although cryoglobulin-related vasculitis occurs in some but not most hepatitis C virus (HCV)-infected persons and is more common in certain ethnic groups. The host genetic basis is not understood and has not been studied in large cohorts. Methods: A genome-wide association study was conducted among 356 HCV RNA positive individuals with cryoglobulinrelated vasculitis and 447 ethnically-matched, HCV RNA positive controls. All cases had both serum cryoglobulins as well as a vasculitis syndrome. A total of 899, 641 markers from the illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically-determined ancestry. Replication of select single nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. Results: The principal clinical manifestations of vasculitis were renal (17%), nerve (69%) and skin (75%). In the discovery panel, a genome-wide significant association was detected on chromosome 6 (Figure). An association with rs9461776 (OR= 2. 14, p=1. 40E-07) between HLA-DRB1 and DQA1 was detected and further replicated (p=0. 01) in additional samples. Conclusions: Polymorphisms in HLA II are associated with cryoglobulin vasculitis in HCVinfected persons.

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Patrice Cacoub - Board Membership: MSD, Roche; Consulting: Vifor, Servier; Speaking and Teaching: Gilead

Alessandra Mangia - Advisory Committees or Review Panels: ROCHE, Janssen, MSD, ROCHE, Janssen, MSD, Boheringer; Consulting: Gilead; Grant/Research Support: Shering-Plough, Shering-Plough

Edgar Charles - Employment: Merck & Co.

David L. Thomas - Grant/Research Support: Merck, Gilead

The following people have nothing to disclose: Anna Linda Zignego, Genevieve L. Wojcik, Marcella Visentini, Massimo Fiorilli, Benjamin Terrier, Rachel Latanich, Salim I. Khakoo, Michael P. Busch, Lynn B. Dustin, Priya Duggal


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Mortality and occurrence of liver-related or extrahepatic complications in patients with HBV- or HCVrelated compensated cirrhosis. A multicenter prospective cohort study in 1654 patients (ANRS CO12 CirVir)

Jean-Claude Trinchet1, Valerie Bourcier1, Cendrine Chaffaut2, Mohand Ait Ahmed1, Patrick Marcellin3, Dominique Guyader4, Stanislas Pol5, Dominique G. Larrey6, Fabien Zoulim7, Dominique Roulot8, Victor de Ledinghen9, Denis Ouzan10, Jean-Pierre H. Zarski11, Pierre Nahon1, Sylvie Chevret2
1Hepatology, Jean Verdier Hospital, APHP, Bondy, France; 2Biostatistics, Saint-Louis Hospital, APHP, Paris, France; 3Hepatology Beaujon Hospital, APHP, Clichy France; 4Hepatology, CHU Rennes Ponchaillou, Rennes' France; 5Hepatology, Cochin Hospital, APHP, Paris, France; 6Hepatology, CHU Montpellier St Eloi, Montpellier, France; 7Hepatology CHU Lyon La Croix Rousse, Lyon, France; 8Hepatology, Avicenne Hospital, APHP, Bobigny, France; 9Hepatology CHU Bordeaux, Haut Lévéque, Bordeaux, France; 10Hepatology, Arnaud Tsank Institute, St Laurent du Var, France; 11 Hepatology, CHU Grenoble Michallon, Grenoble,France

The aim of this cohort was to describe the “natural history” and to assess the incidence and predictive factors of complications in HBV- or HCV-related compensated cirrhosis. Methods: This study involved 35 French centres. Inclusion criteria were histologically proven HCV- or HBV-related cirrhosis, Child-Pugh A, no previous hepatic complication including HCC. Patients were prospectively screened for HCC. Results: A total of 1654 eligible patients were consecutively enrolled from March 2006 to June 2012 [mean age 56 yrs, males 67%; HCV 1308, HBV 315, HCV-HBV co-infection 3l]. Alcohol consumption and metabolic syndrome were more frequent in HCV than HBV patients: 35% vs 16% and 17% vs 8%, respectively. Viral control at inclusion was observed in 376 HCV (28%) and 217 (68%) in HBV patients. During a median follow-up of 34 months, one hundred and five deaths occurred in the whole cohort, more frequently in HCV than in HBV patients (5-yr survival 86% vs. 97%, P=0. 0002), attributable to liver disease in 61(58%) and to extra-hepatic causes in 35 (33%). These latter complications were mainly represented by the occurrence of extra-hepatic cancers (n=61)and cardiovascular events (n=101). Hepatic complications (ascites, digestive bleeding, encephalopathy or bacterial infections) occurred more frequently in HCV than HBV patients (2-yr cumI for a first episode: 5% vs. 2%, P=0. 0004). In HCV patients, the probability of developing at least one of this events was higher in patients with a positive viral load at inclusion (4-yr cumI for a first episode: 22% vs. 12%, P=0. 04) and those cumulating both chronic alcohol consumption and metabolic syndrome (4-yr cumI for a first episode: 42% vs. 17%, P=0. 004). During follow-up, 128 HCC occurred (4-yr cumulative incidence, cumI: 10%). The incidence of HCC was higher in HCV than in HBV patients (4-yr CumI=11% vs. 7%, P=0. 03). Sixty-five percent of HCC were uninodular and 76% were within Milan criteria, leading to the onset of a curative approach as first-line treatment in 54% of cases. In HCV-infected patients, the multivariate model selected as independent predictive factors for death a lower platelet count as well as hypoalbuminemia and a lower platelet count, an older age as well as a positive viral load at inclusion for HCC. Conclusions: Early results of this prospective cohort are: a) complications were more frequent in HCV than HBV patients in whom viral infection control was higher; b) after a follow-up of 3 yrs, non liver-related mortality still concerned one third of deaths; c) HCC screening is effective in this population leading to the early diagnosis of HCC and the onset of curative treatment in most of cases.


Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, JanssenTibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec,

Dominique Guyader - Advisory Committees or Review Panels: Servier; Board Membership: Schering-Plough; Grant/Research Support: Roche, Idera; Speaking and Teaching: Gilead, BMS

Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis; Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis

Dominique G. Larrey - Board Membership: ROCHE, MSD, TIBOTEC/JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI, PFIZER, SERVIER, HELSINN, MMV, BIAL, TEVA; Grant/Research Support: Roche, Boehringer, BMS, GILEAD; Independent Contractor: ABBOTT

Fabien Zoulim - Advisory Committees or Review Panels: Gilead; Consulting: Roche; Grant/Research Support: Gilead, Scynexis, Roche; Speaking and Teaching: Novartis, Roche, Janssen, Bristol Myers Squibb, Gilead

Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen, Gilead, Echosens, Boehringer Ingelheim, Abbvie; Grant/Research Support: Roche, Gilead, Janssen; Speaking and Teaching: Roche, Echosens

Jean-Pierre H. Zarski - Advisory Committees or Review Panels: BMS, Gilead, Janssen Cilag, BMS, Gilead, Janssen Cilag; Consulting: Roche, Scherring Plough, Novartis, Roche, Scherring Plough, Novartis; Speaking and Teaching: Siemens

The following people have nothing to disclose: Jean-Claude Trinchet, Valerie Bourcier, Cendrine Chaffaut, Mohand Ait Ahmed, Dominique Roulot, Denis Ouzan, Pierre Nahon, Sylvie Chevret


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Alcohol Dependence Increases the Mortality Risk in Patients with Hepatitis C

Knut Stokkeland1, 2, Ann-Sofi Duberg3, Scott M. Montgomery4, Johan Franck5, Rolf W Hultcrantz6
1Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine, Visby Hospital, Visby, Sweden; 3Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden; 4Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital in Solna, Stockholm, Sweden; 5Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 6Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden

Background & Aims: Alcohol consumption in addition to hepatitis C is known to be detrimental to the progression of the liver disease. The aims of our study were to evaluate the effects of alcohol dependence in hepatitis C assessed as overall survival and development of severe liver damage. Methods: We linked all reported patients with hepatitis C virus from the Swedish Institute for Infectious Diseases Control up to 2010 to the Patient Register and to the Register on Prescribed Pharmaceuticals. In addition we linked the patients to the Swedish National Council for Crime Preventions' register of convicted person for drunk driving. We defined patients as having alcohol dependence as hospitalized with alcohol dependence, convicted for drunk driving or having been prescribed drugs for alcohol dependence. Results: There were 23 097 men and 6 295 women with hepatitis C who had alcohol dependence. The mortality risk for men with hepatitis C and alcohol dependence were 8. 12 (7. 86-8. 38) compared to men with hepatitis C without alcohol dependence, and for women with hepatitis C and alcohol dependence the risk were slightly lower, 5. 53 (5. 18-5. 90). There was an increased mortality risk for patients with hepatitis C and alcohol dependence with injections as transmission route 6. 85 (6. 61-7. 10), and the highest overall mortality risk was found for patients hospitalized with alcohol dependence, 8. 49 (8. 12-8. 78). In conclusion we found that hospitalizations for alcohol dependence, convictions for drunk driving and prescribed drugs for alcohol dependence are severe risk factors for patients with hepatitis C. Screening for these risk factors are easily done in clinical practice and should warrant careful follow-up considering the risks.


Ann-Sofi Duberg - Advisory Committees or Review Panels: Roche, MSD, Gilead; Grant/Research Support: Janssen; Speaking and Teaching: Roche, Janssen, MSD

The following people have nothing to disclose: Knut Stokkeland, Scott M. Montgomery, Johan Franck, Rolf W. Hultcrantz


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The addition of vaniprevir (MK-7009) to pegylatedinterferon and ribavirin (PR) had a similar healthrelated quality of life (hRqOl) profile compared to PR alone in non-cirrhotic and cirrhotic chronic hepatitis C (CHC) patients with a prior PR failure

Jean Marie Arduino, Norah J. Shire, T. Christopher Mast, Amy Zhou, Peggy Hwang, Niloufar Mobashery
Merck Sharp & Dohme, Corp., North Wales, PA

BACKGROUND Vaniprevir (V), a potent HCV-NS3/4A protease inhibitor, was assessed in combination with PR in non-cirrhotic and compensated cirrhotic CHC patients with a prior PR failure. The decline of HRQOL during PR therapy and rebound of HRQOL post-therapy are well characterized. The aim was to assess whether the addition of V to PR exacerbated the decline of HRQOL during therapy and improved HRQOL post-therapy. METHODS Four treatment regimens of V+PR (N=229) [600 mg bid for 24 weeks, 600 mg bid for 24 weeks followed by PR for 24 weeks, 600 mg bid 48 weeks, 300 mg bid 48 weeks] compared with 48 week PR (N=56) were evaluated. The primary endpoint was sustained viral response at 24 weeks after therapy completion (SVR24). HRQOL, an exploratory endpoint, was assessed using the CHC-specific, chronic liver disease questionnaire (CLDQ-HCV), with Likert scales (1(worst) to 7 (best)), and administered at baseline, 4, 12, 24, 48 weeks on therapy and 24 weeks follow-up. CLDQ-HCV measures Total and Activity/Energy (AEM), Emotion (EMM), Worry (WOM), Systemic (SYM) scores. Means (95% confidence intervals (CI)) and proportions were estimated. RESULTS V+PR showed superior SVR24 rates relative to PR: 63 % to 80% vs 18% (p< 0. 001). V+PR was generally well-tolerated. There were no significant differences in rates of adverse events (AEs) of anemia and skin rash. Gastrointestinal (GI) AEs were higher for V+PR (71% to 90%) than PR (57%) with most mild to moderate in severity. A total of 225 of 285 patients (79%) completed the CLDQ-HCV at baseline and at least once on therapy (V+PR N =1 83, PR N=42). Baseline HRQOL scores were similar between therapy groups (mean Total score (95% CI) for V+PR (5. 1(5. 0, 5. 3)), PR (5. 0(4. 7, 5. 3))). Similar to PR, mean Total scores for V+PR fell rapidly by 4 weeks and remained low until the end of therapy. A significant decline, mean change from last value on-therapy to baseline, was observed in the Total score [V+PR −0. 6(−0. 7, −0. 5), PR −0. 4(−0. 7, −0. 2)] and for the AEM, EMM and SYM scores. AEM had the greatest mean decline [V+PR −1. 1(−1. 3, −0. 9), PR −0. 8(−1. 2, −0. 4)]. At 24 weeks followup, mean change in Total scores rebounded to or above pretherapy values (V+PR 0. 4(0. 2, 0. 6), PR 0. 1(−0. 5, 0. 7)). A numerically higher proportion of V+PR patients (42%) had at least a 0. 5 or greater improvement from their baseline Total score than PR patients (27%, p=0. 28). CONCLUSION Addition of vaniprevir to PR was generally well-tolerated and significantly improved SVR24 rates. Despite an increase in GI AEs, the addition of vaniprevir to PR did not exacerbate the decline in HRQOL during therapy from that observed with PR and improved HRQOL post-therapy.


Jean Marie Arduino - Employment: Merck Sharp & Dohme, Corp.

Norah J. Shire - Employment: Merck

T. Christopher Mast - Employment: Merck Research Laboratories Amy Zhou - Employment: Merck Sharp & Dohme Corp.

Peggy Hwang - Employment: Merck, Merck

Niloufar Mobashery - Employment: Merck; Stock Shareholder: Merck


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Predictors of Liver Disease Progression and Survival in Urban Minority Patients Deemed Ineligible for Hepatitis C Therapy

Manhal J. Olaywi2, Mustafa A. Al Ani1, Aws Aljanabi1, Emily R. Giannattasio1, Hina Zaidi5, Zaid H. Said4, Ghalb Jibara3, Paul J. Gaglio1, John F. Reinus1
1Medicine, Montefiore Medical Center, Bronx, NY; 2Medicine, The Brooklyn Hospital Center, Brooklyn, NY; 3Surgery, Mount Sinai Hospital, New York, NY; 4Medicine, Geisinger Medical Center, Danville, PA; 5Medicine, Long Island Jewish Medical center, New Hyde Park, NY Introduction: Urban minority patients (pts) frequently have chronic hepatitis C (CHC). Effective treatment significantly improves disease prognosis by reducing the incidence of cirrhosis and liver cancer. Only 15% of patients referred to our specialty liver clinic for treatment of hepatitis C have been considered eligible for therapy. The purpose of this study is to investigate the outcome of not treating CHC and the impact of different treatment barriers on disease progression and survival. Methods: We retrospectively reviewed charts of all adult HIVnegative, treatment-naīve patients with chronic hepatitis C evaluated between 01/2001 and 01/2006 who were ineligible for treatment. Demographics and reasons for treatment denial (treatment refusal, comorbid illness, no expected benefit by the provider, substance abuse, psychosocial issues, and non compliance) were collected and analyzed. Progression of liver disease was determined by worsening of fibrosis on biopsy, APRI (AST Platelet Ratio Index), or relevant imaging criteria. Mortality records of the study cohort were obtained from US Social Security and NY Department of Health databases. Statistical analysis was done using SPSS™ software. Results: A total of 981 patients were included in the study. Average age was 44 (10. 8) years and 57. 6% were males. African-Americans (AA) and Hispanics (HS) were 45. 3% and 22. 1%, respectively. Over a median follow up period of 114. 8 ±37. 9 months, 237 (24. 2%) of the study population experienced progression of their liver disease. Progression was more likely to occur in Hispanics (33. 1% vs 21. 0% in AA and 27. 4% in Caucasians, p 0. 001); pts who refused treatment (37. 5% vs 26. 6%, p 0. 025) and pts with comorbid illness (42% vs 23. 8%, p<0. 001). All of these factors remained significant on the multivariate logistic regression analysis [HR: 1. 8 (1. 1-3. 2), 2. 7 (1. 8-4. 1) and 1. 8(1. 1-3. 2), respectively]. The 10-year survival rate of the study cohort was 74. 2 %. On the Kaplan-Meier survival analysis, worse 5-year survival rates were associated with Hispanic race (69. 4% vs 85. 6% in AA and 90. 1% in Caucasians, p <0. 001); comorbid illness (72. 5% vs 89. 9%, p<0. 001); and progression of liver disease (78. 1% vs 89. 6%, p<0. 001). All of these factors retained significance on the multivariate Coxregression analysis [HR: 1. 9(1. 2-3. 0), 2. 6 (1. 9-3. 5) and 2. 0 (1. 4-2. 7), respectively]. Conclusions: 1)The 10 year survival in our study population was 74. 2%. Hispanic race, comorbid medical illness, and liver disease progression were significant predictors of worse survival. 2) Hispanic race, refusal of treatment and comorbid medical illness were associated with progression of liver disease


Paul J. Gaglio - Advisory Committees or Review Panels: Merck, Vertex, Salix; Grant/Research Support: Merck, Gilead, Vertex, Otsuka, Genentech, BI; Speaking and Teaching: Merck, Gilead, Vertex, Salix, Otsuka

The following people have nothing to disclose: Manhal J. Olaywi, Mustafa A. Al Ani, Aws Aljanabi, Emily R. Giannattasio, Hina Zaidi, Zaid H. Said, Ghalib Jibara, John F. Reinus


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Health Care Resources Utilization in Hepatitis C Virus infection and cost associated with adverse events: An Analysis of the Quebec Provincial Drug Reimbursement Program Database

Jean Lachaine1, Marie-Louise Vachon2, Veronique Lamberf-Obry1, Catherine Beauchemin1
1Faculty of Pharmacy, University of Monfreal, Montreal, QC, Canada; 2Department of Infectious Diseases,, Laval University Hospital, Quebec, QC, Canada

Objective The purpose of this study was to estimate, in a real life setting, the health care resource utilization for the treatment of hepatitis C virus (HCV) infection, and more specifically resource utilization for management of the most common adverse events (AE) associated with current treatment. Methods A retrospective study of the Quebec provincial drug reimbursement program (RAMQ) was conducted using a random sample of patients who filed at least one script at the pharmacy for an HCV medication (pegylated interferon and ribavirin (peg-Riba) +/- boceprevir or telaprevir) between January 2007 and December 2012. Data on medical (excluding nurse visits) and pharmaceutical services were extracted from the RAMQ database for all patients. Here we report healthcare resources used during and after HCV treatment in terms of outpatient physician's visits and procedures, emergency visits, hospitalization days and costs associated with adverse events, which included medical services and medications. Results A total of 1, 102 patients who used at least one HCV medication were included in the study. The average age was 46. 5 years (SD=10. 7) and the proportion of men was 64. 9%. The number of patients who used Peg-Riba only, Peg-Riba + boceprevir and Peg-Riba + telaprevir was 1, 027 (93. 2%), 53 (4. 8%) and 40 (3. 6%) respectively. A total of 18 patients (1. 6%) required a subsequent HCV treatment during the study period. The mean duration of treatments was 27. 8 weeks (SD=12. 3). During HCV treatment, the average number of health care resources used per patient was 12. 8 physician's visits and procedures, 1. 0 hospitalization day and 0. 9 emergency visits. Average number of health care resources used per patient during the one-year period following initiation of HCV treatment was 18. 7 physician's visits and procedures, 2. 0 hospitalization days and 1. 4 emergency visits. While receiving HCV treatment, 196 (17. 8%) of patients required erythropoietin, 361 (32. 8%) received rash treatments and 548 (49. 7%) were treated for depression. Estimated costs associated with management of these three adverse events were CDN$10, 666, CDN$78 and CDN$268 per patient respectively. Conclusion HCV treatment is associated with significant health care resource utilization. A high proportion of patients experienced adverse events for which management was associated with substantial additional costs, especially the anemia treatment. Thus, the cost of adverse events should be considered in future treatment options.


Jean Lachaine - Grant/Research Support: Gilead Sciences Marie-Louise Vachon - Consulting: Gilead, vertex, merck, roche, BI Catherine Beauchemin - Independent Contractor: Gilead The following people have nothing to disclose: Veronique Lambert-Obry


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Genetic Variants in Interleukin 28B are associated with Diabetes and Diabetes-related Complications in Patients with HCV

Fasha Kanwal, Donna White, Shahriar Tovokoli-Tabasi, Li Jiao, Shubhada Sansgiry David J. Ramsey, Jill B. Kuzniarek, Hashem ElSerag
Michael E DeBakey VA and Baylor College of Medicine, Houston, TX

Background: Data suggest that host interleukin 28B (IL28B) genotype polymorphisms are associated with insulin resistance in patients with hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. We investigated whether variation within IL28B gene is associated with clinical outcomes related to insulin resistance—diabetes and diabetesrelated complications. Methods: We prospectively recruited patients with HCV seen in liver clinics at a single center between 2009 and 2012. We classified patients on the basis of their IL28B genotype (rs12980275) as AA, AG, and GG where A is the favorable allele. We defined patients with diabetes and related complications if they had > 2 outpatient or >1 inpatient ICD-9 codes for diabetes and diabetic complications (diabetes-related nephropathy, retinopathy, circulatory complications) within 2 years of recruitment. In sensitivity analyses, we alternatively defined diabetes on the basis of fasting blood glucose > 126 mg/dl or patients' self-report. We then performed multivariable logistic regression analysis adjusting for patients' age, race, body mass index, and stage of hepatic fibrosis (by Fibrosure) to isolate the effect of IL28B on diabetes. Results: A total of 416 participants were included (mean age: 56 years; 25% African-American; 38% F3-F4 fibrosis, 77% HCV genotype 1). Of these, 40% were homozygous for the favorable allele of IL28B, 46% were heterozygous, and 14% were homozygous for the unfavorable alleles. Prevalence of diabetes was significantly higher in patients with at-least one unfavorable allele than those with both favorable alleles (33% vs. 22%, p=0. 03). Similarly, significantly more patients with any unfavorable allele experienced diabetes-related complications than those with both favorable alleles (12. 5% vs. 5%, p=0. 01). This association was consistent across whites and African Americans and did not change after adjusting for demographics, body mass index, and stage of fibrosis (adjusted odds ratio for favorable vs. any unfavorable allele=0. 62, 95% CI=0. 38-. Redefining diabetes as part of sensitivity analyses did not change the results. Conclusion: Compared to patients who are homozygous for favorable IL28B genotype (at rs12980275), HCV+ patients with any unfavorable allele have a higher prevalence of diabetes and its related complications, independent of degree of hepatic fibrosis. IL28B genotype information may be used to counsel patients regarding their individualized risk for diabetes. The relationship between IL28B and diabetes may also shed light on pathways involved in the development of insulin resistance in patients with HCV.


Hashem El-Serag - Consulting: Gilead

The following people have nothing to disclose: Fasiha Kanwal, Donna White, Shahriar Tavakoli-Tabasi, Li Jiao, Shubhada Sansgiry, David J. Ramsey, Jill B. Kuzniarek


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Association of self-reported change in alcohol use behavior with changes in percent carbohydrate deficient transferring (%CDT), ethyl glucuronide (EtG) and ethyl sulfate (EtS) levels in Veterans with Hepatitis C

Eric Dieperink3, Bret Fuller2, Samuel B. Ho1, Paul Thuras3, Kelly McMaken3, Kern Shira4, Rebecca Lenox2, Michelene M. Wasil1, Carl Isenhart3, Timothy R. Morgan4, Peter Hauser4
1VA San Diego Healthcare System, San Diego, CA; 2Portland VA Medical Center, Portland' OR; 3Minneapolis VA Medical Center' Minneapolis' MN; 4Long Beach VA Medical Center, Long Beach, CA

The primary objective of this study is to determine the association between structured self-reported changes in alcohol use with changes in three biological measures associated with alcohol consumption. Carbohydrate deficient transferrin (%CDT), ethyl glucuronide (EtG) and ethyl sulfate (EtS) are biomarkers for alcohol consumption but little data exist regarding accuracy in reflecting self-reported alcohol use in patients with HCV. Methods: Data from two studies examining alcohol interventions in veterans with HCV examined the relationship between self-reported drinking and biological measures of alcohol consumption. Both studies are randomized-controlled trials for veterans with HCV. The first is a study of motivational enhancement therapy (MET) compared with a control condition to reduce drinking in veterans with HCV. The other study tested the drug baclofen to reduce alcohol consumption. Studies were conducted at the Portland, Minneapolis, Long Beach and San Diego VA Systems. Baseline alcohol use was measured with two methods: 1)self-report 30-day Time Line Follow Back and 2) three biological measures, the %CDT, EtG, EtS. Patients were included who met eligibility criteria including having HCV and drinking more than 7 drinks per week or having one heavy drinking day (4+ drinks) 2 weeks prior to study enrollment. Results: Data from a total of 252 individuals across the 4 sites and 2 studies were included in the analysis. The majority of the sample was male (99. 9%), white (88%) and all were Veterans. The mean age was 58. The pairwise correlations between the 7, 14 and 21 day cumulative drink totals from the TLFB and the %CDT, EtG, and EtS were calculated. The correlations between 7day alcohol consumption and biological measures were %CDT (r=. 3061), EtG (r=. 2583) and EtS (r=. 3371). For the 14day interval: %CDT (r=. 3065), EtG (r=. 2257) and EtS (r=. 2950); and for the 21-day interval %CDT (r=. 3l28), EtG (r=. 2110) and EtS (r=. 3128). All pairwise correlations were significant at p<. 01 level. Other measures of alcohol intake via TLFB and AUDIT-C, and the 12 week follow up are also presented. Conclusions: Results suggest that the biological measures and self-report measures are robust and correlate moderately. The ethyl-sulfate and %CDT were stronger indicators of drinking than was EtG, even though the latter is more often used clinically as a measure of alcohol consumption. While the correlations for %CDT and EtS were similar, the %CDT had more missing data due to “BPV” indicators in which the result cannot be discerned as being caused by specifically by alcohol use. Results show that that EtS is a better measure of alcohol use in Veterans with HCV.


Samuel B. Ho - Grant/Research Support: Roche, Genentech, Vital Therapies, Aspire Bariatrics

Timothy R. Morgan - Grant/Research Support: Merck, Vertex, Genentech, Gilead, Bristol Myers Squibb

The following people have nothing to disclose: Eric Dieperink, Bret Fuller, Paul Thuras, Kelly McMaken, Kern Shira, Rebecca Lenox, Michelene M. Wasil, Carl Isenhart, Peter Hauser


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A novel framework for understanding susceptibility to hepatotropic infections in low resource settings

Alain B. Labrique, Christopher D. Heaney, Brittany Kmush, Kenrad Nelson
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

We present a novel ‘systems' framework to explain increased susceptibility to hepatotrophic infections in low resource settings where host exposures to hepatotoxic agents of environmental and biological nature coexist. The JiVitA Research Project has prospectively followed the pregnancies of ∼60, 000 women since 2007 from Northern Bangladesh. A 1100 subsample was selected for biochemical analysis. Plasma at 1st trimester (TM), 3rd TM and 3 months post-partum (PP) of these women were tested for anti-Hepatitis E Virus (HEV) IgG using an NIH in-house immunoassay to the open reading frame-3 of HEV. 40 women were identified as seroconverters, with 39 seroconverting between the 3rd TM and 3 months PP. 40 age, parity and sector of residence-matched controls were selected from the non-seroconverters in the sub-study. A panel of micronutrients and cytokines were analyzed in the plasma from the 1st TM, 3rd TM and 3 months PP of these 80 women. Urinary metal concentrations, including arsenic, were also analyzed from the 1st and 3rd TM. The seroconverters were found to have lower circulating zinc (p=0. 04) as well as a greater prevalence of anemia (p=0. 045), as measured by circulating hemoglobin, and vitamin D deficiency (p=0. 08) when compared to the controls at the 1st TM. Throughout pregnancy, seroconverters displayed higher concentrations of both pro(IFN-y, IL-1b, IL-2, IL-8, IL-12 and TNF-α) and anti-inflammatory (IL-4, IL-5, IL-10, IL-13) cytokines compared to the controls. Inorganic arsenic concentrations were similar in the 1st TM for seroconverters (65. 6μg/L) and controls (64. 7μg/L). The seroconverters maintained these concentrations through the 3rd TM (61. 6μg/L) while the concentration in the controls decreased (35. 9μg/L). The seroconverters displayed marked differences in their micronutrient, cytokine and arsenic profiles at early pregnancy, before seroconversion occurred. The opportunity to study host factors in seroconverters prior to infection is rare. This cohort represents a unique opportunity to examine susceptibility to hepatotropic infections across multiple, interconnected axes-nutrition, toxin exposure, immunocompetence and infection. We propose a novel conceptual framework of host-level risk factors for hepatotrophic pathogens such as HEV. Arsenic intake, from food and water, along with micronutrient deficiencies, from inadequate diet and a high infectious disease burden, may lead to dysregulated cytokine expression and immunologic compromise. This dysregulation in combination with hepatotoxicity from arsenic and heavy metal exposure lead to immunosuppression, increasing the risk of HEV and other hepatotrophic pathogen infection and illness.


The following people have nothing to disclose: Alain B. Labrique, Christopher D. Heaney, Brittany Kmush, Kenrad Nelson


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FibroTest (FT) performances for the diagnostic and prediction of varices and decompensation in hepatitis C cirrhotic patients

Thierry Poynard1, Jordi Bruix2, Marika Rudler1, Mona Munteanu3, Massimo Colombo4, Eugene R. Schiff5, Clifford A. Brass6, Janice K. Albrecht6
1APHP UPMC Groupe Hospitalier Pitié-Salpêfriére, Paris, France; 2BCLC Group; Liver Unit, Hospital Clinic of Barcelona, University of Barcelona; DIBAPS, Centro de Investigación Biomédica en Red de Hepatologίa y Enfermedades Digestivas, Barcelona, Spain, Barcelona, Spain; 3BioPredictive, paris, France; 41st Division of Gastroenterology, Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico, Universitá degli Studi di Milano, Milan, Italy; Center for Liver Diseases, Milano, Italy; 5University of Miami School of Medicine, Miami, FL; 6Merck, Whitehouse Stafion, NJ

Aim. Garcia-Tsao et al (Hepatology 2010) encouraged moving beyond the characterization of cirrhosis as a single stage and instead thinking of cirrhosis as a series of critical steps that culminate in hepatic decompensation. FT has been validated as a marker of METAVIR fibrosis stages from F0 to F4 using biopsy, methods without gold standard and liver related mortality. The aim of the present study was to validate FT as a marker of compensated cirrhosis (F4) without varices, vs compensated with varices (F5) and vs decompensated (F6) defined by the following events: ascites, variceal hemorrhage (VH), encephalopathy, jaundice and HCC. Methods Previously non-responder patients of the EPIC3-F4 randomized trial of maintenance PEG-IFN vs no-treatment (Bruix Gastro 2011) were included in this ancillary study if they had at least one baseline interpretable FT and endoscopy. The FT accuracy for the diagnosis of F5 among cirrhotic patients was assessed transversally using endoscopy at baseline. The FT predictive value for F5 was assessed longitudinally using the occurrence of varices among patients without baseline varices (F4). For F6, occurrences were decompensation predetermined clinical events (ascites, encephalopathy, Child C, variceal bleeding, HCC) adjudicated by an independent committee of experts blinded to treatment and FT. Results From the 626 patients with biopsy-confirmed cirrhosis randomized in the trial (RCT), 574 were included in the diagnostic study, 286 Treated by PEG-INTRON and 288 Observed. Characteristics of 574 pts of the diagnostic study were similar to those not-included. At baseline 73 F5 pts (with varices) had higher FT [0. 82 (95%CI 0. 79-0. 86)] than 501 pts F4 (without varices) [0. 77 (95%CI 0. 75-0. 78); P=0. 007]. At 5 years (mean 32 months) FT was significantly associated with occurrence of F6 (clinical events n=61), including HCC (n=24), and occurrence of F5 (varices progression, n=30) (Table). FT predictive values persisted after adjustment (Cox) on treatment randomization for shown endpoints and also for ascites, death/transplantation. Conclusion: In CHC non-decompensated cirrhotic patients FT is associated with presence of esophageal varices and is predictive of the 5 year occurrence of varices (7% FT>0. 85 19% FT>0. 95) and decompensation (12% FT>0. 85 and 36% FT>0. 95).

Incidence of complications Kaplan-Meier % 5 year (95% Cl) Risk Ratio (Cox) =P value
Baseline FibroTest (n)VaricesClinical eventHCC
<=0. 74(191)2 (0-3)1=Reference5 (2-9)1=Reference3 (0-5)1=Reference
>0. 74-0. 85 (128)5(1-9) 3. 0(0. 7-12. 1) =. 127(3-12)1. 3 (0. 5-3. 3) =. 502 (0-5) 0. 9 (0. 2-3. 8) =•90
>0. 85-0. 95 (198)7(3-11)4. 4(1. 2-15. 5). 0212(8-17) 2. 4(1. 1-5. 1) =. 044(1-7)1. 4 (0. 4-4. 5) =•52
>0. 95 (57)19(7-31) 11. 1 (2. 9-42. 0) =. 000436 (22-50) 7. 56 (3. 48-16. 39 =. 000120 (8-33) 7. 8 (2. 6-23. 5) =. 0002


Thierry Poynard - Advisory Committees or Review Panels: Merck; Grant/Research Support: BMS, Gilead; Stock Shareholder: Biopredictive

Marika Rudler - Speaking and Teaching: Gilead Sciences, BMS, Gore, Eumedica Mona Munteanu - Employment: Biopredictive


Eugene R. Schiff - Advisory Committees or Review Panels: Anadys, Bayer, Bristol Meyers, Conatus, Daiichi Sankyo, Gilead, Johnson and Johnson, Merck, Novartis, Pfizer, Salix, Sanofi Aventis, Wyeth, Vertex, Anadys, Bayer, Bristol Meyers, Conatus, Daiichi Sankyo, Gilead, Merck, Novartis, Pfizer, Salix, Sanofi Aventis, Wyeth, Vertex, Anadys, Bayer, Bristol Meyers, Conatus, Daiichi Sankyo, Gilead, Johnson and Johnson, Merck, Novartis, Pfizer, Salix, Sanofi Aventis, Wyeth, Vertex, Anadys, Bayer, Bristol Meyers, Conatus, Daiichi Sankyo, Gilead, Johnson and Johnson, Merck, Novartis, Pfizer, Salix, Sanofi Aventis, Wyeth, Vertex; Grant/Research Support: Abbott, Bristol Meyers, Conatus, Debio Pharm, Labcore, Merck, Roche, Salix, Sanofi Aventis, Vertex, Gilead, Wyeth, Abbott, Bristol Meyers, Conatus, Debio Pharm, Johnson and Johnson, Labcore, Merck, Roche, Salix, Sanofi Aventis, Vertex, Gilead, Wyeth, Abbott, Bristol Meyers, Conatus, Debio Pharm, Labcore, Merck, Roche, Salix, Sanofi Aventis, Vertex, Gilead, Wyeth, Abbott, Bristol Meyers, Conatus, Debio Pharm, Labcore, Merck, Roche, Salix, Sanofi Aventis, Vertex, Gilead, Wyeth

Clifford A. Brass - Employment: Merck, Merck, Merck, Merck; Stock Shareholder: Merck, Merck, Merck, Merck

The following people have nothing to disclose: Jordi Bruix, Janice K. Albrecht


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Association of polymorphisms of vitamin D metabolic pathway related genes with treatment response of chronic hepatitis C to Pegylated interferon-alfa based therapy in Asian population

Kessarin Thanapirom1, Sirinporn Suksawatamnuay1, Pisit Tangkijvanich2, Sombat Treeprasertsuk1, Srunthron Akkarathamrongsin3, Yong Poovorawan3, Piyawat Komolmit1
1Medicine, Chulalongkorn University, Bangkok, Thailand; 2Biochemistry, Chulalongkorn University, Bangkok, Thailand; 3Pediatric, Chulalongkorn University, Bangkok, Thailand

Background/aims: Recently, low serum 25(OH) vitamin D level has been proposed as a predictor of poor treatment response with standard therapy in patients with chronic hepatitis C (CHC) infection. A number of genetic polymorphisms in the vitamin D cascade have been reported to affect vitamin D level, signaling and stratification. We aimed to determine the association between the functionally genetic polymorphisms of vitamin D cascade and outcome of treatment(SVR) with pegylated interferon-alpha based therapy in CHC patients in Asian population. Methods: 296 Asian patients with CHC treated with pegylated interferon-alfa based regimen were enrolled. Twelve tagging SNPs across the vitamin D metabolic pathway related genes, including CYP27B1, CYP2R1, Vitamin D binding protein (GC) and Vitamin D receptor (VDR), were genotyped (Table 1). Haplotypes of Bsml, Apal and Taql (BAT) were also analysed. Results: Of these, 196 patients(66. 2%) achieved SVR. 122 patients (41. 2%) were infected with HCV genotype 1 or 4. In all HCV genotypes, the association of these polymorphisms and outcome of treatment were not demonstrated, except for CYP27B1(−1260) CC genotype which revealed higher trend to have poor treatment response(Tablel). The BAT G-G-T or A-T-C haplotypes (OR=1. 704, 95% CI=1. 509-1. 923, p-value=0. 009) were increased risk of treatment failure. In difficult-to-treat HCV genotypes (1 and 4), only CYP27B1 CC genotype was strongly associated with poor treatment response (SVR: CC vs. non-CC; 37%vs. 62%, p-value=0. 026). Multivariate analysis revealed age (OR=1. 05, 95%CI = 1. 004-1. 092, p-value=0. 03) and CYP27B1 CC genotype (OR=4. 08, 95% CI=1. 532-10. 88, pvalue=0. 005) were independent predictor of non-SVR. Conclusions: This study suggested that in Asian patients with CHC, only CYP27B1(−1260) CC genotype was strongly associated with poor treatment response to standard therapy, particularly in difficult-to-treat genotype. These findings support clinical evidence of the role of vitamin D on treatment response in CHC infection and, as a strong predictor of unfavorable outcome, the CC variant of CYP27B1(−1260), might be used to stratify a group of difficult to treat patient who initially required a better treatment regimen.

Results of vitamin D metabolic pathway related gene polymorphisms and prediction of poor sustained virological response in all HCV genotype.

  1. *Difficult-to-treat genotypes, **Difficult-to-treat genotype&multivariate analysis

Vitamin D gene and SNPsOdds ratio (95%CI)P-value
CYP27B1 C>A (rsl0877012) CC (vs. non-CC) CYP27B1 C>A (rsl0877012) CC (vs. non-CC)* CYP27B1 C>A (rsl0877012) CC (vs. non-CC)**1. 728 (0. 989-3. 020) 2. 850 (1. 171-6. 934) 4. 080 (1. 532-10. 88)0. 05 0. 03 0. 005
CYP2R1 (rs2060793) TT (vs. non-TT) CYP2R1 C>T (rsl2794714) CC (vs. non-CC)0. 988(0. 456-2. 137) 0. 802(0. 461-1. 396)1. 00 0. 48
GC C>A (rs4588) CC (vs. non-CC) GC G>T (rs7041) GG (vs. non-GG) GC G>A (rs222020) GG (vs. non-GG) GC A>C (rs2282679) AA (vs. non-AA)1. 135(0. 643-2. 002) 1. 072(0. 608-1. 890) 1. 264(0. 663-2. 409) 1. 388(0. 777-2. 482)0. 67 0. 88 0. 50 0. 31
VDR FokI T>C (rs2228570) TT (vs. non-TT) VDR Bsml G>A (rsl544410) GG (vs. non-GG) VDR Apal G>T (rs7975232) GG (vs. non-GG) VDR Taql T>C (rs731236) TT (vs. non-TT) VDR Tru91 G>A (rs757343) GG (vs. non-GG)1. 104(0. 577-2. 113) 1. 116(0. 607-2. 053) 1. 133(0. 689-1. 863) 1. 518(0. 634-3. 636) 1. 156(0. 668-1. 999)0. 74 0. 76 0. 70 0. 40 0. 68


The following people have nothing to disclose: Kessarin Thanapirom, Sirinporn Suksawatamnuay, Pisit Tangkijvanich, Sombat Treeprasertsuk, Srunthron Akkarathamrongsin, Yong Poovorawan, Piyawat Komolmit


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Global Distribution of HCV Genotypes

Homie Razavi, Sarah Hindman, Erin Gower, Chris Estes
Center for Disease Analysis, Louisville, CO

Background: HCV genotype is an important factor influencing treatment decisions and clinical outcomes. To better understand the distribution of HCV genotypes at the global level, a comprehensive literature search was conducted. Methods: Global and regional databases were searched for studies reporting HCV genotypes by country. A systematic scoring system was used to assess the quality of each data source. The highest ranking study was selected for each country. When necessary, a secondary data source was used to determine the breakout of sub-genotypes 1a and 1b. The results were analyzed by both the geographic and the World Bank income regions. Results: Country-specific genotype distributions were available for approximately 35% of all countries, which collectively represented over 75% of the global population. Globally, genotype 1(G1) was the most common (44% of HCV cases), followed by G3 (26%) and G4 (14%). Genotype 1b was the most common sub-type accounting for 27% of all infections. However, significant regional, country, and local variations existed. Infections in North America, Latin America, and Europe were predominately G1(65-75%) with G1b accounting for 25%, 30%, and 50% of all cases respectively. Sub-Saharan Africa also had a large G1 population (65%) with 5% G1b and 12% G5. North Africa and the Middle East had a large G4 population (75%), which was attributable to the high prevalence of G4 in Egypt. When Egypt was excluded, the genotype distribution of this region was more similar to Europe with 60% of the HCV population being G1. The Asia Pacific region was predominately G1 (40%) followed by G3 (35%). largely driven by the HCV infected populations in India and Pakistan. G1b accounted for 30% of all infections in the region. Less differentiation was observed when data were analyzed by country income level with two exceptions. First, ten percent of infections in lowincome countries were G6, driven by the prevalence of this subtype in Southeast Asia. Second, genotypes 3 & 4 dominated the lower-middle-income countries (40% and 27% respectively) due to the genotype distribution of India, Pakistan, and Egypt. Conclusion: Although this analysis found genotype distributions for 75% of the world's population, 65% of the countries did not have published data. Country level strategies are needed to manage HCV disease burden. Until pan-genotypic therapies are available, genotyping will be required to determine the therapy type, duration, and expected response rate. Studies in low-income and lower-middle-income countries are needed where less than 20% report HCV genotype distribution.


Homie Razavi - Consulting: Gilead, Abbott, Boehringer Ingelheim Chris Estes - Consulting: Abbott, Gilead

The following people have nothing to disclose: Sarah Hindman, Erin Gower


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Iron overload and glucose abnormalities in chronic hepatitis C virus infection: phlebotomy lowers risk of newonset diabetes

Hirohide Miyachi, Motoh Iwasa, Yoshinao Kobayashi, Yoshiyuki Takei
Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan

Aim: Recent studies have shown that moderate hyperferritinemia is a common finding in chronic hepatitis C (CHC) and that excess hepatic iron accumulation contributes to liver injury and enhances the risk of hepatocellular carcinoma. On the other hand, given that cross-sectional studies have consistently reported a high prevalence of glucose abnormalities in patients with CHC, iron overload has been suggested to explain this association. Therefore, we evaluated the relation of serum ferritin and hepatic hepcidin expression with glucose metabolic parameters and whether long term phlebotomy lowers the risk of new-onset diabetes in patients with CHC. Methods Study 1: Hepatic hepcidin mRNA expression was measured in 28 CHC patients and their relation with clinical parameters and histological findings was evaluated. Study 2: Ninety-two patients without type 2 diabetes were divided into two groups: a phlebotomy group underwent an initial period of phlebotomy and maintenance phlebotomy was performed; data obtained in CHC patients that declined to receive phlebotomy were used as control. Results Study 1: Hyperferritinemia was associated with high AST and ALT levels and serum ferritin levels also increased in parallel with the grade of histological fibrosis. High hepatic hepcidin expression was associated with high BMI (p<0. 05), FPG (p<0. 01), and HbAlc levels (p<0. 05) in CHC patients. Study 2: The mean follow-up period was 38. 9 months (6-108 months). Serum levels of ferritin and ALT significantly decreased from 204 ng/ml to 22 ng/ml and from 68. 4 IU/l to 51. 0 IU/l after phlebotomy, whereas in control group neither serum ferritin nor ALT decreased. The values of visceral fat area did not change during the study (phlebotomy group, before 101. 1 cm2, after 101. 4 cm2; control group, before 97. 4 cm2, after 93. 4 cm2). A total number of five patients developed newonset type 2 diabetes; log-rank test revealed that long-term phlebotomy tends to lower the risk of new-onset diabetes compared with untreated patients (p=0. 063). In addition, high ferritin levels (cut-off of 184. 9 ng/ml) were able to predict further episodes of diabetes in CHC patients (p<0. 01). Conclusions: Hepatic hepcidin over-expression is associated with over-weight and glucose abnormalities, that high-ferritin level is a risk for the development of diabetes and that reduction of body iron stores may lower the risk of new-onset diabetes in patients with CHC. Management of iron overload is important to prevent new-onset diabetes and may offer a possible approach to improve prognosis of patients with CHC.


The following people have nothing to disclose: Hirohide Miyachi, Motoh Iwasa, Yoshinao Kobayashi, Yoshiyuki Takei


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Economic Burden And Outcomes Of Patients Hospitalized With Hepatitis C In The United States

Ruhong Luo1, Christian D. Stone2
1Internal Medicine, University of Nevada School of Medicine, Las Vegas, NV; 2Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV

Background: There are approximately 3. 2 million patients with chronic Hepatitis C virus (HCV) infection in U. S. With progressive disease and complications of HCV-related cirrhosis, hospitalizations are a common occurrence in these patients. Our objective was to investigate the economic burden and outcomes of patients hospitalized for hepatitis C in U. S. Methods: Using data from the Nationwide Inpatient Sample, from 2005-2009, we identified by ICD-9-CM codes patients hospitalized with a primary diagnosis of liver related diseases and a secondary diagnosis of HCV infection. The main outcome of interest was in-hospital mortality. Hospital service utilization was estimated based on the length of stay (LOS) and hospital charges. The trends of the volume of HCV-related hospitalization and demographic characters of the patients were analyzed. Independent risk factors for mortality were identified using logistic regression. Considering the possibility of the co-existence of different risk factors for mortality, a prognostic model was built by discriminant analysis to predict in-hospital outcome. Results: A total of 415, 153 cases HCV-associated hospitalization were identified. Over 5 years, the hospitalization rate increased by 21. 8%, with the annual rate of growth of 4. 4%. The proportion of non-Caucasian patients increased. A majority (65%) was located in the south and west regions of the U. S and 90% were admitted in urban hospitals. In-hospital mortality declined from 8. 2 to 7. 2%. Median LOS (4 days) was unchanged, while hospital charges increased by 40. 6% with an average annual growth rate of 8. 1%. 3. 7% of patients had prior liver transplant. The most common liver- associated procedure was paracentesis, performed in 37. 5% of patients, followed by gastrointestinal endoscopy (13. 1%). 2. 8% of patients were hospitalized for orthotopic liver transplantation (OLT). Acute respiratory failure was the greatest independent risk factor for mortality (OR=7. 3), followed by renal failure (OR=4. 5), septicemia (OR=4. 1) and acute liver failure (OR=2. 7). Other major independent risk factors (OR>1. 5) for mortality included age>65 years old, esophageal varices, liver carcinoma, coinfection of HIV, hypovolemia, acidosis and coagulopathy. Based on the major risk factors for mortality, our prognostic model predicted survival during hospitalization with the sensitivity of 58. 3% and the specificity of 91. 8%. Conclusion: In spite of decreasing in-hospital mortality, hospitalization volume and charges related to hepatitis C have increased substantially from 2005-2009. Increased focus on prevention measures in chronic HCV patients to reduce hospitalization is warranted.


Christian D. Stone - Speaking and Teaching: Abbvie, Janssen, UCB The following people have nothing to disclose: Ruihong Luo


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Hepatitis E infection in French pregnant women: a prospective study

Christophe Renou1, Christophe Locher2, Vincent Gobert2, Jeanine Savary3, 4, Anne-Marie Roque-Afonso3, 5
1Service Hepatologie, Centre Hospitalier de Hyéres, Hyéres, France; 2Service Hepatologie, Centre Hospitalier de Meaux, Meaux, France; 3Service de Virologie, AP-HP Hopital Paul Brousse, Villejuif, France; 4UMRS785, Univ Paris-Sud, Villejuif, France; 5Unit 785, Inserm, Villejuif, France

In developing countries, hepatitis E affects a large proportion of the population and pregnant women are especially prone to fulminant hepatitis. By contrast, no severe HEV infection has been reported in pregnant woemen from high income countries. The objective of the study was to determine HEV seroprevalence and assess risk factors for HEV contamination in French pregnant women. Patients: HEV serology (IgG and IgM; Adaltis, Milan, Italy et Wantai, Beijing, China) was performed in early pregnancy and in postpartum among women attending two hospitals in Northern and southern France. A questionnaire listing the different risk factors for HEV infection and complications during pregnancy was given at the time of sampling. Results: Serological data were available for 184 and 60 women from Northern and Southern France, respectively. According to the assay (Adaltis vs. Wantai), detectable IgG (index >1. 1) were found in 1, 6 and 5, 4% women from Northern France and 6, 6 and 25, 7% women from Southern France. A north-south gradient of seroprevalence is suggested with the Adaltis test (p = 0. 064) and confirmed with the Wantai test (p = 0. 0017). Women with detectable anti-HEV IgG were older: 33+/-5 vs. 29+/-5 years (p=0. 05). The lifestyle questionnaire did not find differences between women with and without IgG regarding trips abroad (p = 0. 5), consumption of seafood (p = 0. 38), possession of pets (p = 0. 18) or consumption of pork liver (p = 0. 14). However, the possession of a well seemed more common in positive women (p = 0. 059), as well as a history of transfusion (p = 0. 007). Postpartum serology was available for 70 seronegative women in early pregnancy. No seroconversion was observed in an average interval of 7 + / −2 months. Conclusion: HEV seroprevalence in early pregnancy is significantly related to the assay used for determination, age, geographic region of residence and, surprisingly, with a history of transfusion. The lack of contact with HEV during pregnancy may be linked to the reduced interval between the two blood samples or potential changes in lifestyle that must be explored.


The following people have nothing to disclose: Christophe Renou, Christophe Locher, Vincent Gobert, Jeanine Savary, Anne-Marie Roque-Afonso


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Hepatitis C Virus Infection in Patients with Cancer: A Single-Institution Experience in 642 Patients

Harrys A. Torres, Parag Mahale, Issam I. Raad, Dimitrios P. Konfoyiannis
Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Hepatitis C Virus (HCV) infection in cancer patients (pts) is a neglected topic. Guidelines do not include recommendations for pts with cancer as only limited data are available. We sought to determine the characteristics and outcome of HCV-infected pts with cancer. Methods: Records of HCV seropositive pts with any type of cancer seen at MD Anderson Cancer Center (2008-2011) were retrospectively reviewed. Only those with detectable HCV RNA were further analyzed. Pt characteristics were evaluated using descriptive statistics. Categorical variables were compared using x2 test or Fisher's exact test. Results: Of 90, 614 new cancer pts seen during the study period, 1, 291 (1. 4%) had positive HCV antibody. HCV RNA was detectable in 642 of 744 (58%) pts tested. Of these 642 pts, most were men (68%), Caucasians (65%), and had genotype 1 HCV (66%). Solid tumors predominated (n=462 or 72%) as underlying cancer; 38% had hepatocellular carcinoma (HCC). Among 173 (42%) pts with hematologic cancer, 61% had lymphoma. Drug abuse was the most frequent risk factor for HCV (60%), being more common in males than females (65% vs 50%; p=. 005). Acquiring HCV trough blood transfusion was less common in males than females (28% vs 44%; p=. 001). Most pts (54%) had stage 3/4 fibrosis at baseline. Only 35 (5%) pts were tested for IL28B polymorphism, with a predominance of CT genotype noted (49%). HCV therapy (HCV-T) was administered in 98 (15%) pts, mainly as a combination of INFα (pegylated or not) and ribavirin (n=77 or 79%). None of them received direct-acting antivirals. In all pts, HCV-T was administered once cancer remission was achieved. HCV-T was frequently associated with adverse events (AEs) (54%), mainly hematologic (40%). Dose reduction of HCV-T (53%) and hematopoietic growth factors (54%) were regularly used to manage such AEs. HCV-T was interrupted in 41% pts, mostly due to hematologic toxicity (43%). The majority of pts (77%) had >1 AEs, including psychiatric (21%) and gastrointestinal (19%) AEs. Sustained virological response (SVR) occurred in 27 (35%) pts. HCC developed, as a second neoplasia, in 32 of the 491(8%) pts with different baseline cancer. Conclusions: This is the largest series studying HCV-infected pts with any type of cancer. The epidemiology mirrors that of the US general population. Once in remission, infected cancer pts can receive HCV-T, and their exclusion from clinical trials is unnecessary as the efficacy and tolerability of HCV-T are comparable to those reported in other special populations (e. g, HCV-HIV coinfected pts). Development of HCC as second primary malignancy is not uncommon among those with different underlying cancer.


Harrys A. Torres - Advisory Committees or Review Panels: Merck, Vertex, Novartis, Astellas, Pfizer, Genentech; Grant/Research Support: Merck, Vertex

The following people have nothing to disclose: Parag Mahale, Issam I. Raad, Dimitrios P. Kontoyiannis


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Hepatitis C Virus Birth Cohort Testing and Linkage to Care (HepTLC) in a large Washington DC Medical Center

Alexander Geboy1, Sandeep Mahajan2, Ike Fleming1, Allison Daly1, Candice Sewell2, Carmella Cole2, Won Kyoo Cho2, Dawn Fishbein2
1MedStar Health Research Institute, Washington, DC; 2Medicine, MedStar Washington Hospital Center, Washington, DC

Purpose: CDC recently recommended that all persons born within 1945 一 1965 (Birth Cohort) be hepatitis C (HCV) tested at least once, given a 3. 25% prevalence rate in that age group, higher than the 1. 6% national average. We hypothesize that Birth Cohort HCV rates for our urban hospital clinic will be significantly higher than those previously published. Methods: Beginning December 2012, we established a HCV testing program in the Primary Care Clinic at MedStar Washington Hospital Center, with CDC grant funding (HepTLC), to sequentially test in this Birth Cohort, link directly to care and create a sustainable testing program. Eligibility includes: born between 1945-1965, without predetermined risk factors, and not previously HCV tested or positive. Notifications to providers are sent via the EMR whereby they test patients for HCV with either a serum ELISA or rapid finger stick ELISA; confirmatory testing is done in those positive. Serum testing is covered by insurance; rapid testing from the grant. Patients testing HCV antibody positive are linked to care with either an Infectious Diseases specialist or Gastroenterologist, regardless of HCV RNA status. Comparisons are performed between those HCV-infected and not infected using chi-square and Student's t-tests. Results: As of April 24, 2013, 1, 993 patients were eligible for testing; 611 (31%) have been tested, 857 (43%) cancelled/no-showed for their appointment, and 525 (26%) were not tested, despite having a visit. Of the 611 tested, 60 (9. 8%) were HCV infected (HCV Ab+); 1 8/29 (62%) were RNA positive, indicating chronic HCV. In the entire cohort, mean age was 58. 2+5. 6 years, 90% were African American, 64% were women and 56% had public insurance (Medicaid or Medicare). In those HCV positive, mean age was 58. 6+4. 5 years, 92% were African American, 40% were women and 78% had public insurance. There were more men (OR 3. 1[CI95 1. 8-5. 4]) and persons with public insurance (OR 3. 1[1. 6-5. 9]) in those HCV infected. Conclusion: HCV prevalence of 9. 8% in this Washington, DC, urban clinic is significantly higher than the known rate of 3. 25% in the Birth Cohort. These rates are very concerning as those positive are not previously known to be at risk or infected. The Birth Cohort testing initiative by the CDC is of utmost importance and highlights the likely drastic underestimation of HCV infection, primarily among African Americans. With testing readily available, the benefit of diagnosing HCV before symptoms appear will likely be cost-effective and facilitate early treatment and cure. In so doing, we can prevent disease progression and possibly eradicate this viral infection at a population level.


Dawn Fishbein - Advisory Committees or Review Panels: Boehringer Ingelheim Pharmaceuticals

The following people have nothing to disclose: Alexander Geboy, Sandeep Mahajan, Ike Fleming, Allison Daly, Candice Sewell, Carmella Cole, Won Kyoo


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Therapeutic plasma exchange as a method of transmission of Hepatitis E Virus in solid organ transplant recipients

Vincent Mallet1, Anne-Marie Roque-Afonso2, Rebecca Sberro3, Anaϊs Vallet-Pichard1, Bénédicte Deau4, Alix Portal1, Lisette Hauser5, Christophe M. Legendre3, Stanislas Pol1
1Hepatologie, Université Paris Descartes, APHP, Hopital Cochin, INSERM U. 1016, Paris' France; 2Virologie, Université Paris Sud, APHP, CHU Paul Brousse, Unite Propre de Recherche de l'Enseignement Superieur (Upres) 3541, Villejuif, France; 3Transplantation renale, Universite Paris Descartes, APHP, CHU Necker, Inserm, Paris, France; 4Hématologie, Universite Paris Descartes, APHP, CHU Cochin, Inserm U. 1016, Paris, France; 5Unite de Gestion des Risques et de la Qualité, Etablissement Francois du Sang, SaintDenis, France

BACKGROUND Hepatitis E Virus (HEV) is an emerging infectious disease in industrialized countries. An unexplained high incidence of HEV infections, which can evolve to cirrhosis and death, has been reported in solid organ transplant (SOT) recipients. Acute antibody-mediated rejection and thrombotic thrombocytopenic microangiopathy in SOT recipients are sometimes treated with therapeutic plasma exchange (TPE). HEV may be transmitted by transfusion of red blood cells and platelets. The prevalence of anti-HEV antibodies ranges from 10-50% in blood donors in western countries and 10% of plasma fractionated pools test positive for HEV-RNA. These pools are pathogen-inactivated with solvent-detergent incubation or Amotosalen. The present study was designed to investigate the relation between transmission of HEV in SOT recipients and the use of TPE during the peritransplantation period. METHODS Posttransplant frozen samples were tested for the presence of HEV genome (Ceeram, La Chapelle sur Erdre, France) and anti-HEV IgG and IgM antibodies (Wantai, Beijing, China) and pre-transplant frozen samples from SOT recipients with detectable posttransplant anti-HEV antibodies and/or HEV RNA were tested for the presence of anti-HEV IgG antibodies. Frozen aliquots of all blood products received by SOT recipients who developed post-transplant chronic HEV infection were screened for the presence of HEV. The incidence of HEV infection was compared between SOT recipients treated or not with TPE. RESULTS 347 patients received a SOT from October 2010 to December 2011 in a tertiary care center in Paris, France. 48 (14%) were treated with TPE. 267 SOT recipients had available post-transplant frozen samples. 83/267 (31%) had detectable post-transplant anti-HEV IgG. Among these patients, 74/83 (9 missing samples, bringing the population from 267 to 258) had available pre-transplant frozen samples, allowing the identification of 26/258 (10%) post-transplant HEV infections (25 anti-HEV IgG seroconversions, including 2 chronic HEV infections, 1 seropositive and 1 seronegative). TPE was found to be associated with transmission of HEV (Risk Ratio 2. 62; 95% CI, 1. 09 to 6. 31). 2/26 patients, both treated with TPE, developed chronic HEV infection and the same HEV strain was detected in a unique Amotosalen-treated plasma for one patient; the other case is under investigation. CONCLUSION TPE is a mode of transmission of HEV in SOT recipients. Fresh frozen plasma, including those inactivated with the last generation products, may transmit HEV. Plasma should be tested for HEV, especially those destined to SOT recipients and other susceptible recipients.


Vincent Mallet - Board Membership: MSD, Janssen; Speaking and Teaching: Roche, Gilead, BMS

Anal's Vallet-Pichard - Independent Contractor: Schering Plough, Gilead, BMS, Roche

Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis; Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis

The following people have nothing to disclose: Anne-Marie Roque-Afonso, Rebecca Sberro, Benedicte Deau, Alix Portal, Lisette Hauser, Christophe M. Legendre


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Barriers to cure for hepatitis C: Data from a large integrated health system

Kimberly Ann Brown1, David R. Nerenz2, Renee Atkinson2, David B. Rein3
1Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI; 2Center for Health Policy and Health Services Research, Henry Ford Hospital, Detroit, MI; 3NORC, University of Chicago, Chicago, IL

Introduction: Current anti-viral therapy for hepatitis C results in SVR rates of 70-90%. Several factors may prevent patients from accessing treatment. Aims: The aims were to Evaluate linkages between HCV screening and treatment, calculate the “missed opportunity” at each transition, and analyze patient characteristics which influenced the “missed opportunity” at each transition. Methods: Patients > age 18 with a first time hepatitis C antibody test and any primary care visit from 2005-2010 were included. Data regarding HCVRNA testing, patient referral, patient visit, and treatment initiation (defined as “transitions”) as well as patient factors including age, race, gender, income, marital status, psychiatric diagnoses and number of co-morbidities were recorded at each “transition”. Attrition at each transition from antibody testing through SVR was calculated and factors associated with attrition were analyzed. Results: 566 patients with anti-HCV positive test results were identified with 109 excluded: 39 (6. 9%) died, 69 (12. 2%) left the system. 458 patients were included for analysis. 37l/458 (81%) patients with a positive HCVAb had a documented HcVrnA test. Patients with more comorbidities were significantly less likely to receive testing (OR 0. 82, p=0. 049). 308/371 patients (83%) were positive for HCVRNA. 183/309 (59. 4%) were referred to a hepatologist. Patients with more co-morbidities were significantly less likely to be referred (OR 0. 73, p=0. 001). 117/183 (63. 9%) of the patients referred to a hepatologist had a documented visit. Patients were more likely to have a documented hepatology visit if they were married (OR 2. 85, p=0. 027) or older at the time of initial testing (OR1. 05, p=0. 035). 21/117 (17. 9%) patients with a documented hepatology visit received treatment. None of the patient or treatment factors evaluated were significantly associated with initiation of treatment. 8/21 (38%) treated patients achieved an SVR. Of those patients initially identified as antiHCV positive, only 1. 7% (2. 6% of those with a documented RNA positive result), achieved an SVR. Conclusions: Within a large health care system with relatively easy access to specialist care, the “lost opportunity” for SVR is significant. Only 21% of eligible patients with a positive hepatitis C antibody received further testing and transitioned to specialty care with only 17. 9% of these patients receiving treatment. Thus, the “true” SVR of patients positive for hepatitis C would be calculated at 2. 6%. Patient co-morbidities, marital status and age at initial antibody testing were significantly associated with at least some transition steps of HCV care.


Kimberly Ann Brown - Advisory Committees or Review Panels: CLDF, Merck, Salix, Gilead, Vertex, Novartis, Genentech, Gilead, Janssen, Novartis, Salix; Consulting: Blue Cross Transplant Centers, Salix; Grant/Research Support: CLDF, Gilead, Exalenz, CDC, BMS, Bayer-Onyx, Ikaria, Hyperion, Merck; Speaking and Teaching: Salix, Merck, Genentech, Gilead, CLDF, Vertex

The following people have nothing to disclose: David R. Nerenz, Renee Atkinson, David B. Rein


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Seroprevalence of Hepatitis C Virus Infection by Year of Birth in Spain: Any impact of the USA CDC Recommendation of HCV Testing among Persons Born during

Alvaro Mena1, Luz Moldes2, Angeles Castro1, Angelina Cañizares2, Héctor Meijide3, José D. Pedreira1, Germán Bou2, Eva Poveda1
1Division of Clinical Virology, INIBIC-Complejo Hospitalario Universitario A Coruña, A Coruna, Spain; 2Service of Microbiology, INIBIC-Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; 3Service of Internal Medicine, Hospital Chiron, A Coruna, Spain

Background: The Centers for Disease Control and Prevention (CDC) of USA recommends one-time testing of HCV infection in persons born during 1945-1965, a population with a disproportionately high prevalence of HCV infection and related disease in the USA. Herein, we evaluated the seroprevalence of HCV infection by year of birth in a large cohort of subjects attending at a reference medical area in Spain to analyze the potential impact of this recommendation in our population. Methods: All assays results entries for HCV serological markers ordered at our lab from primary care and specialized physicians between 2008 and 2012 were recorded. Our center covers a medical care area of 501, 526 citizens. The year of birth was also documented. Results: A total of 92, 143 antiHCV-Ab results were generated during the last 5 years with a global prevalence of anti-HCV+ of 8. 6%. The yearly rate has remained stable during the last 5 years: 8. 2% (2008), 7. 4% (2009), 7. 8% (2010), 8% (2011), and 10. 1% (2012). Among anti-HCV+ individuals, 51. 7% were male with a mean age of 45±18. Figure records the overall prevalence of anti-HCV-Ab+ by year of birth in this population. The highest prevalence of HCV antibodies were observed in persons born before 1940 and between 1960-1975. This last period coincided with the year of birth of those individuals affected by the huge intravenous drug use epidemic in the eighties in Spain. Conclusions: The prevalence of HCV infection varies by year of birth in our population. Conversely to that observed in the USA, there was no evidence of increased HCV prevalence in subjects born between 1945 and 1965. In our population, the highest rates of HCV infection are observed in persons born before 1940 and between 1960-1 975. Different historical and social circumstances might explain it, including the huge intravenous drug use epidemic occurred in the eighties in Spain. Therefore, the recommendation made by the USA CDC of HCV testing among persons born during 1945-1965 might not be applicable to other populations.

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The following people have nothing to disclose: Alvaro Mena, Luz Moldes, Angeles Castro, Angelina Canizares, Hector Meijide, Jose D. Pedreira, German Bou, Eva Poveda


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HCV Patients with Diabetes Have Significantly Higher Average APRI Compared with Nondiabetic HCV Patients: Results of a National Lab Test Database Analysis

Carol Smyth1, Desfry Sulkes1, Jason Bhan1, Jc Muyl1, Tatiana Sorokina1, Nancy Reau2
1Medivo, New York, NY; 2University of Chicago Medicine, Chicago, IL

Purpose The relationship between hepatitis C (HCV) and type 2 diabetes mellitus (DM) is complex. Recent studies suggest that DM is associated with more severe fibrosis in patients with chronic HCV. To assess the potential impact of DM on hepatic fibrosis in patients with HCV, we used the AST/platelet ratio index (APRI) to compare APRI values in HCV patients with and without diabetes. The APRI equation is: aspartate aminotransferase (AST)/upper limit of normal of AST (40 IU/L)/platelet count X 100. Research suggests that the stages of liver damage are associated with the APRI as follows: <0. 5 (no/minimal hepatic fibrosis), 0. 51一1. 5 (fibrosis grades 1-4); >1. 5 (cirrhosis). Methods We analyzed lab test results for HCV patients with and without DM in the nationwide Medivo Database Repository (Medivo Inc., New York, NY) between Jan 1-Dec 31, 2012. Out of >2. 1 million patients in the database, there were >8, 000 patients with HCV; 3, 071 HCV patients had both AST and platelets tested simultaneously and were included in the analysis. Of these, 385 patients had DM and 2, 686 were nondiabetic. 2X3 between-subjects ANOVA was performed to identify the main effect of diagnosis (HCV without DM vs. HCV with DM) and the interaction between diagnosis and estimated stage of liver damage as indicated by APRI. Logistic regression analysis was performed to assess the impact of DM on the risk of fibrosis or cirrhosis in HCV patients. Results ANOVA revealed the main effect of diagnosis; HCV patients with DM had a significantly higher APRI than nondiabetic HCV patients (1. 21 vs. 1. 02; P=0. 02). Interaction between diagnosis and estimated stage of liver damage was not significant (P = 0. 65). Regarding the risk of fibrosis associated with DM, we found that HCV patients with DM were as likely as those without DM to have an APRI within the range associated with fibrosis (OR =1. 15, P = 0. 23). However, HCV patients with DM were 36% more likely to have an APRI > 1. 5, a score associated with cirrhosis, than those without DM (OR =1. 36, P = 0. 02). Conclusion Patients with HCV and DM have a higher average APRI and a higher risk for an APRI of >1. 5 (associated with cirrhosis) than those without DM. We conclude that DM is likely to be associated with faster progression of hepatic fibrosis/development of cirrhosis in HCV patients, but more study is needed.


Carol Smyth - Employment: Medivo

Destry Sulkes - Stock Shareholder: Medivo, Inc.

Jason Bhan - Employment: Medivo

Nancy Reau - Advisory Committees or Review Panels: Genentech, Kadmon, Jannsen, Vertex, Idenix; Consulting: IHEP; Grant/Research Support: Vertex, Gilead, abbott

The following people have nothing to disclose: Jc Muyl, Tatiana Sorokina


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Blocking the HCV entry factor NPC1L1 via ezetimibe improves HCV outcomes

Jennifer E. Layden1, Lishan Cao2, Peter Corcoran1, Frances Weaver2, Susan L. Uprichard1
1Medicine, Loyola University Medical Center, Maywood, IL; 2Hines VA Hospital, Maywood, IL

Background. We recently reported that the cellular cholesterol uptake receptor NPC1L1 is an HCV entry factor and that blocking NPC1L1 uptake with the FDA approved cholesterol lowering medication, ezetimibe inhibits HCV entry in vitro and in chimeric mice challenged with HCV. Hence, we tested the hypothesis that that ezetimibe usage has a protective effect on HCV outcome. Methods. Using the National Health and Nutrition Examination Survey (NHANES) and the VA nationwide database systems retrospective analyses were performed examining the association of ezetimibe use with HCV seroprevalence. Initial analysis of NHANES data from 2003-2010 was used to estimate HCV seroprevalence among individuals on/off ezetimibe, excluding HIV infected individuals. Statistical methods were appropriately used to correct for the complex population based sampling and study design. For the VA database, nationwide data was used from 2003-2011 to define the cohort of patients tested for HCV antibodies. Medication data included use and dates of ezetimibe and Methadone. Patients who were prescribed ezetimibe after the HCV antibody test date were excluded. Additional co-variables included age, gender, and race. Results. In the NHANES, there was a total of 15, 613 subjects with known HCV antibody results and ezetimibe use information. The HCV seroprevalence weighted estimate was 1. 7% (consistent with nationwide estimates) in those not taking ezetimibe, but only 0. 2% in those on ezetimibe (p=. 02). This association held when excluding individuals who knew of their HCV sero-status prior to study participation. In the VA database, 2, 945, 119 individuals had usable HCV antibody test results. In multi-variable logistic regression controlling for age, gender, and race, ezetimibe use was protective against HCV sero-positivity with a Odd's Ratio of 0. 67 (0. 650. 70; p<0. 001). The seroprevalence of HCV for patients on ezetimibe was 6% compared to 9% for those not on ezetimibe (p<0. 001). Conclusions. In conclusion, there was an association with ezetimibe usage and lower HCV seroprevalence, suggesting the possibility that ezetimibe use may protect against acute infection. However, further studies controlling for other known co-variables is underway. Additional studies examining the effect of ezetimibe on HCV clearance, treatment response, viral RNA levels, and the disease progression are warranted.


The following people have nothing to disclose: Jennifer E. Layden, Lishan Cao, Peter Corcoran, Frances Weaver, Susan L. Uprichard


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Mortality and Barriers to Treatment in Urban Minority Patients Deemed Ineligible for Hepatitis C Therapy

Manhal J. Olaywi2, Mustafa A. Al Ani1, Aws Aljanabi1, Emily R. Giannattasio1, Ghalib Jibara5, Zaid H. Said3, Hina Zaidi4, Paul J. Gaglio1, John F. Reinus1
1Medicine, Montefiore Medical Center, Bronx, NY; 2Medicine, The Brooklyn Hospital Center, Brooklyn, NY; 3Medicine, Geisinger Medical Center, Danville, PA; 4Medicine, Long Island Jewish Medical Center, New Hyde Park, NY; 5Surgery, Mount Sinai Hospital, New York, NY

Introduction: Urban minority patients frequently have hepatitis B Effective treatment significantly improves disease prognosis by reducing the incidence of cirrhosis and liver cancer, but the outcome of treatment denial has not been well studied. Only 15% of patients referred to our specialty liver clinic for treatment of hepatitis C have been considered eligible for therapy. The purpose of this study is to determine mortality in urban minority patients denied HCV therapy and the relationship of mortality to liver disease and barriers to its treatment. Methods: We retrospectively reviewed charts of all adult HIV-negative, treatment-nalve outpatients with chronic hepatitis C evaluated between January, 2001 and June, 2006 who were deemed not to be candidates for treatment. Reasons for denial (barriers) were recorded, and mortality incidence as of March, 2011 was determined by search of the US Social Security database. Causes of death and associated conditions in deceased individuals were found by review of the NY Department of Health database of death certificates. Statistical analysis by SPSS™ software. Results: Records of 980 patients with treatment barriers were reviewed: 57. 6 % male, 45. 3% African-American (AA), 22. 1% Hispanic (HS). 23% of these persons died within ten years of evaluation: cause of death unknown-17%, related to liver disease-38%, unrelated to liver disease-45%. No specific barrier was associated with liver-related mortality. Genderrelated barriers included, active substance abuse: 11. 5% of females, 23. 8% of males (p=0. 001); noncompliance: 53. 4% of males, 45% of females (p=0. 006); comorbid illness preventing therapy: 23. 8% of females, 17. 9% of males (p=0. 015). Ethnicity-related barriers included, treatment refusal: 12. 6% of AA, 2. 9% of HS (p=0. 004); substance abuse: 26. 9% of HS, 14. 6% of AA (p=0. 007); psychosocial issues: 31. 6% of HS, 19. 4% of AA. There were no ethnic differences in compliance. Conclusions: 1) A significant percentage of urban minority patients who are not candidates for HCV treatment die within ten years of evaluation. 2) Mortality was most often unrelated to liver disease suggesting that treatment denial may have been appropriate, but more than one third of patients denied treatment die of liver disease. 3) Noncompliance and substance abuse are more common barriers to therapy in males than in females while comorbid illness is a more common barrier in females. 4) AA patients are most likely to refuse treatment while HS patients are most likely to have psychosocial treatment barriers.


Paul J. Gaglio - Advisory Committees or Review Panels: Merck, Vertex, Salix; Grant/Research Support: Merck, Gilead, Vertex, Otsuka, Genentech, BI; Speaking and Teaching: Merck, Gilead, Vertex, Salix, Otsuka

The following people have nothing to disclose: Manhal J. Olaywi, Mustafa A. Al Ani, Aws Aljanabi, Emily R. Giannattasio, Ghalib Jibara, Zaid H. Said, Hina Zaidi, John F. Reinus


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Frequency and factors associated with advanced HCVrelated liver disease at the time of presentation for care at the referral center of Beaujon between 2000-2010

Blaise K. Kutala, Tarik Asselah, Nathalie Boyer, Dominique Valla, Patrick Marcellin
Service d'hépatologie, Hopital Beaujon, Chichy, France

Background: Chronic hepatitis C, is a major cause of chronic liver disease globally, may progress to cirrhosis, liver failure, hepatocellular carcinoma (HCC), and premature liver-related death. Our objective was to determine factors associated with a presentation for care with an advanced stage of disease in patients who were recently diagnosed or who delayed their contact for care after diagnosis. Methods: We reviewed data of 3042 HCV infected patients seen at our unit between January 2000 and December 2010. 925 patients who did not meet inclusion criteria were excluded (absence of biopsy, HCC at presentation, coinfection and already treated for HCV). Advanced disease stage was defined as bridging fibrosis (F3) or cirrhosis (F4) as shown at liver biopsy at the time of presentation for care. Patients were separated into two groups: Recent testing (RT) with a HCV diagnosis ≤1year at presentation for care; and delayed presentation (DP) with a HCV diagnosis >1 year at presentation for care. We used multinomial logistic regression to determine the factors associated with advanced stage at late testing and delayed presentation. Results: Among of 2117 naive patients, 1091 had late RT and 1026 had DP. 484 patients with an advanced stage of disease at presentation: 217 (20%) in RT group and 267 (26%) in DP group. Proportion of sex male were similarly in two groups (58% in RT vs 56% in DP) Median age were 46 years in RT vs 48 in DP (p=<. 0001). Factors associated with RT were: age above 40 years (Odds ratio, OR=2. 34; confidence intervals 95% (CI)= [1. 49-3. 67], born in an endemic area (OR=1. 51; Ci95%= [0. 83-2. 75]), male non-immigrant OR=2. 74; CI95% [1. 694. 44], used alcohol intake (OR=2. 96; CI95% [1. 99-4. 40]). Factors associated with a delayed presentation for care were: patients who initiated HCV care between 2000-2005 years (OR=1. 5; CI95% [1. 10-2. 03]), drug user status (OR=1. 5; CI95% [1. 00-2. 51]), male immigrant (OR=2. 14; CI95% [1. 263. 65]), single status (OR=2. 30; CI95% [1. 60-3. 29]). The overall survival rate at 5 and 10 years in late testing group compared with delayed presentation were 97% and 88% vs 94% and 78% (log rank p=0. 0001). Conclusion: A considerable proportion of HCV-infected patients present to care with advanced HCV disease. Recent testing, rather than a delay presentation in initiating care after earlier HCV testing, is the main determinant of presentation to care with advanced HCV disease. The factors associated with delay presentation to care differ from those associated with late testing except alcohol problem. Different strategies should be developed to optimize early access to care and testing in immigrant and user drug population.


Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen

Nathalie Boyer - Board Membership: MSD, JANSSEN; Speaking and Teaching:

Dominique Valla - Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, JanssenTibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec,

The following people have nothing to disclose: Blaise K. Kutala


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Association between chronic hepatitis C infection and vascular risk and function

Puraskar Pateria1, Helena Ching 1, Gerry C. MacQuillan1,2, Gary P. Jeffrey1, 2, Gerald Watts2, 3, David J. Speers1,2, Leon Adams1, 2
1Western Australian Liver Transplantation services, Sir Charles Gairdner Hospital, Perth, WA, Australia; 2School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia; 3School of Medicine and Pharmacology, Royal Perth Hospital unit, University of Western Australia, Perth, WA, Australia

Vascular disease is the third leading cause of death in patients with chronic hepatitis C (CHC) infection. CHC may lead to atherosclerosis by increasing pro-atherogenic inflammatory cytokines and insulin resistance in genotype 1 patients. We wished to determine whether patients with CHC infection are at increased risk of atherosclerotic disease and whether genotype or anti-viral treatment modifies this risk. Methods: We performed a case-control study of CHC patients and age and gender matched healthy controls. Subjects underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness [aortic augmentation index (Alx) and carotid-femoral pulse wave velocity (PWV)], endothelial dysfunction [brachial artery flow mediated dilatation (FMD) and dilatation post glycerol trinitrate administration (GTNMD)] and carotid intima media thickness (CIMT). Assessment was repeated in CHC patients undergoing treatment, with pegylated interferon and ribavirin, 18 months after initiation of treatment. Results: Fifty cases [mean age (±SD): 47. 5 (±9) years, 54% males] with CHC were matched to 22 healthy controls [mean age (±SD): 46. / (±11) years, 55% males]. Thirty-three cases (57. 5%) had CHC genotype 1 infection. Baseline vascular risk factors (blood pressure, BMI, serum HDL-cholesterol, LDL-cholesterol, glucose, HOMA) were not significantly different between cases and controls. Measures of arteria丨 stiffness, endothelial dysfunction and carotid thickness were not different between cases and controls (p>0. 2 for all). However, among cases, patient with genotype 1 infection had greater endothelial dysfunction with lower FMD as compared to non-genotype 1(8. 2±3. 5% verses 10. 9±5. 2%, p=0. 03) and evidence of subclinical atherosclerosis with higher right mean CIMT (0. 6±0. 1mm verses 0. 5±0. 07mm, p=0. 04). Vascular risk and function was not related to the presence of cryoglobulins. Twelve patients received anti-viral treatment and 7 (58%) patients achieved SVR. All patients showed significant improvement in endothelial function with GTNMD post treatment (20±6% verses 7. 9±3. 1%, p=0. 003) and a trend towards improved vascular stiffness (PWV 7. 9±1. 6 m/s verses 7. 3±1. 8m/s, p=0. 07). The improvement in PWV was significant in patients who achieved sustained viral response (PWV 7. 4±1. 1 m/s verses 6. 5±0. 6m/s, p=0. 04) but not in those who did not clear (PWV 8. 5±1. 9 m/s verses 8. 3±2. 4 m/s, p=0. 07). Conclusion: Measures of vascular risk differ between CHC patients according to genotype and treatment, however are not different when compared to healthy controls.


Gary P. Jeffrey - Advisory Committees or Review Panels: MSD, Novartis

The following people have nothing to disclose: Puraskar Pateria, Helena Ching, Gerry C. MacQuillan, Gerald Watts, David J. Speers, Leon Adams


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Burden of Birth Cohort in Chronic Hepatitis C Virus infection in the U. S.: A Population-Based Cohort Study

W. Ray Kim, Chung II Wi, Joseph J. Larson, Terry Tnerneau
Mayo Clinic College of Medicine, Rochester, MN

Background: Hepatitis C virus (HCV) infection remains a major source of morbidity and mortality from liver disease in the United States. While the Center for Disease Control and Prevention recently revised their policy for screening to include all Americans born between 1945 and 1965 (birth cohort), population data are scarce to guide implementation of the policy. Aims: Based on a unique population-based registry of community residents with newly identified chronic HCV infection, we analyze the diagnosis and treatment pattern in the community. Methods: Using the resources of Rochester Epidemiology Project (REP), we have developed and updated a registry that includes all residents in Olmsted County who were diagnosed with chronic HCV infection between January 1, 1990 and December 31, 2010. The case ascertainment was supplemented by laboratory databases at Mayo Clinic and Olmsted Medical Center, which were queried to identify all Olmsted County residents who had any positive tests for hepatitis C. Result: There were a total of 645 patients (64% male) diagnosed with chronic hepatitis C in Olmsted County during the study period, including 436 (68%) who belonged in the 19451965 birth cohort. 329 patients (51%) were identified since 2000, but the number of patients being newly diagnosed with chronic hepatitis C each year has decreased with the peak in around 2000. Patients being diagnosed with HCV infection since 2000 are more likely to have identified traditional risk factors such as injection drug (65%) or intranasal cocaine use (42%), compared to those diagnosed before 2000 (51% and 24% respectively). The mean age of patients at the time of HCV diagnosis increased over time (p<0. 01). These trends seem partly to be attributable to aging of birth cohort. In both eras, the proportion of birth cohort did not change significantly (66% vs. 70%, p=0. 27). They are more likely to have 1 or more identified risk factors compared to those outside the birth cohort (84% vs. 69%, p<0. 001). Overall, 153 patients (24%) received HCV treatment with no change in the proportion receiving treatment between eras (23% vs. 25%, p=0. 56). Conclusion: The number of patients being diagnosed with chronic hepatitis C in the community is decaresing and the proportion of patients who undergo treatment remains unacceptably low. This may indicate that implementation of birth cohort screening is needed to discover asymptomatic hepatitis C patients in the community. Effective follow-up strategy will be also necessary in order for the birth cohort screening to yield public health benefits.


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

The following people have nothing to disclose: Chung II Wi, Joseph J. Larson, Terry Therneau


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Integrated care for high risk psychiatric and substance use disorder patients with hepatitis C increases overall SVR rates: Final results of a prospective mulnsite randomized trial

Samuel B. Ho1, 2, Erik J. Groessl1, 2, Norbert Brau3, Ramsey Cheung4' Courtney M. Sanchez1, Nicole Campbell1, Mohso Sklar1, Lin Liu1, 2, Tyler E. Phelps4, Sonja Marcus3, Michelene M. Wasil1, Amelia S. Tisi3, Lia K. Huynh4, Shannon Robinson1, 2
1VA San Diego Healthcare System, San Diego, CA; 2University of California, San Diego, La Jolla, CA; 3VA Medical Center, Bronx, NY, Bronx, CA; 4VA Palo Alto Healthcare System, Palo Alto, CA

Objectives: Psychiatric and substance use disorders are common in patients with hepatitis C and have been barriers to receiving antiviral treatment. Our objective was to determine if an Integrated Care protocol could increase the proportion of HCV patients who receive antiviral treatment and acheive a sustained virologic response (SVR). Methods: This prospective, randomized trial was conducted at three VA medical centers in large metropolitan areas. Patients at risk for active psychiatric and substance use disorders who attended VA HCV clinics between 5/09-2/11 were recruited and randomized to usual care (UC) or integrated care (1C). The IC intervention included a co-located mid-level mental health practitioner who provided brief mental health interventions and case management according to a formal protocol. The primary outcome was the proportion of all patients with SVR in each group. Univariate and multivariate analysis were used to examine predictors of outcomes. Results: The 364 randomized patients (1 82 IC, 1 82 UC) were 98% male; race included 38% White, 39% African American, 18% Hispanic; 49% homeless in prior 5 years; 27% with Audit C >/=4; 57% PTSD risk positive; mean depression (BDI) score=15. 4; 12% HIV-coinfected; and 80% HCV genotype 1. There were no significant baseline differences between groups. More patients in IC initiated antiviral therapy, (32% vs. 18. 7%, OR 2. 036, p=0. 004); and more patients in IC achieved a SVR (15. 5% vs. 7. 2%, OR 2. 365, p=0. 015). Of those initiating antiviral therapy, 27% in each group received direct acting antivirals. Patients in IC vs. UC tended toward higher completion of planned therapy duration (53 vs. 44%) and higher end-of-treatment virologic response (53 vs. 47%). Independent predictors of SVR in multivariate analysis included IC (OR 2. 49, p=0. 013), genotype non-1 (OR 2. 63, p=0. 01), prior liver biopsy (OR 2. 48, p=0. 01), and prior psychiatric disorder diagnosis (OR 0. 46, p=0. 027). Adverse event data indicate non-significant trends toward fewer hospitalizations, hospitalized days, and emergency room visits for all IC patients regardless of receipt of antiviral therapy. There were 10 deaths in UC compared to 6 deaths in IC; one occurred during antiviral treatment in UC. Conclusions: Integrated care for HCV patients at risk for psychiatric and substance use disorders results in an increase of 149% in the odds of SVR. The intervention is safe, with a trend for lower numbers of major adverse events in those receiving integrated care. Funding: Veterans Affairs HSR&D IIR-07-101-3; ClinicalTrials. gov NCT00722423


Samuel B. Ho - Grant/Research Support: Roche, Genentech, Vital Therapies, Aspire Bariatrics

Erik J. Groessl - Stock Shareholder: Gilead, Bristol Myers Squibb

Norbert Brau - Advisory Committees or Review Panels: Janssen; Grant/Research Support: BMS, Gilead, Vertex; Speaking and Teaching: Vertex, Onyx

The following people have nothing to disclose: Ramsey Cheung, Courtney M. Sanchez, Nicole Campbell, Marisa Sklar, Lin Liu, Tyler E. Phelps, Sonja Marcus, Michelene M. Wasil, Amelia S. Tisi, Lia K. Huynh, Shannon Robinson


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Differential impact of common risk factors of fibrosis progression in chronic hepatitis C

Sina Rueger1, Pierre-Yves Bochud2, Jean-Francois Dufour3, Beat Mullhaupt4, David Semela5, Markus H. Heim6, Darius Moradpour7, Andreas Cerny8, Raffaele Malinverni9, Zoltan Kutalik10, 11, Francesco Negro12, 13
1Medical Genetics, University of Lausanne, Lausanne, Switzerland; 2Infectious Diseases, University Hospital and University of Lausanne, Lausanne, Switzerland; 3Hepatology, University of Berne, Berne, Switzerland; 4Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland; 5Gastroenterology, Canton Hospital St Gallen, St Gallen, Switzerland; 6Gastroenterology and Hepatology University Hospital of Basel, Basel, Switzerland; 7Gastroenterology and Hepatology, University Hospital and University of Lausanne, Lausanne, Switzerland; 8Epatologia, Clinica Moncucco, Lugano, Switzerland; 9Pourtales Hospital, Neuchatel, Switzerland; 10Institute of Social and Preventive Medicine, University Hospital and University of Lausanne, Lausanne' Switzerland; 11 Swiss Institute of Bioinformatics' Lausanne, Switzerland; 12Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland; 13Gastroenterology and Hepatology, University Hospitals of Geneva, Geneva, Switzerland

Background and Aim: The natural course of chronic hepatitis C shows a wide range of inter-individual variability, depending on cofactors: some patients develop cirrhosis in a few years from infection, while others may never (or slowly) progress. Given the importance of targeted interventions in patients at risk of progression, we assessed the relative contribution of cofactors of liver fibrosis progression in 801 patients with chronic hepatitis C enrolled in the Swiss Hepatitis C Cohort Study (495 [62%] males, 306 [38%] with Metavir fibrosis stages F3 or F4), for whom an estimated date of infection and at least one liver biopsy were available. Methods: We used (1) a linear regression model to test for differences in fibrosis pro gression rate (FPR; stage increase per year) by risk factors, and (2) a Cox proportional hazard model to test for differences in duration of infection until fibrosis stage 3/4, by risk factors. Explanatory variables included sex, age at infection, HCV genotype, BMI, excess alcohol drinking (≥40 g/day for >5 yrs), HIV coinfection or diabetes. Results: By linear regression, sex, age at infection, HCV genotype and BMI independently predicted progression. Infection at a later age (effect size β = 1. 032 [1. 027, 1. 036]), male sex (p =1. 32 [1. 18, 1. 40]) and HCV genotype 3 (p =1. 26 [1. 15, 1. 38]) increased FPR, while BMI >25 slightly decreased FPR (p = 0. 92 [0. 85, 1. 00]). The variance attributable to each risk factor was 18. 7% for age at infection, 3. 2% for sex, 2. 6% for HCV genotype, 0. 3% for BMI and 75. 2% for residual unknown factors. Using the same model, but limited to the 442 patients with an estimated duration of infection >20 yrs, age at infection, male sex and HCV genotype still remained in the model, but additionally HIV (p = 1. 25 [1. 04, 1. 51]) and excess alcohol drinking (β =1. 12 [1. 00, 1. 26]) contributed. However, in this case, the variance attributable to unknown factors increased to 87. 5%. The survival model confirmed the importance of sex, age at infection, and HCV genotype, but additionally revealed excess alcohol drinking (HR=1. 75 [1. 30, 2. 37]) and HIV coinfection (HR=2. 60 [1. 69, 4. 00]) as main drivers of fibrosis progression. Conclusions: Common cofactors impact on liver disease progression in hepatitis C, but their influence varies according to stage or duration of infection. Moreover, the variance in FPR attributable to common cofactors is minor, and that the vast majority of this variance is unaccounted. More efforts should be dedicated to understanding the pathogenesis of fibrosis progression in hepatitis C.


Pierre-Yves Bochud - Speaking and Teaching: MSD, Gilead

Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gilead, Jansse, Novartis, Roche

Beat Mullhaupt - Consulting: MSD, Novartis, Gillead, Janssen; Grant/Research Support: Bayer, Roche, MSD, Boehringer

Francesco Negro - Advisory Committees or Review Panels: Roche, MSD, Gilead, Boehringer Ingelheim; Grant/Research Support: Roche, Gilead

The following people have nothing to disclose: Sina Rueger, David Semela, Markus H. Heim, Darius Moradpour, Andreas Cerny, Raffaele Malinverni, Zoltan Kutalik


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Hepatitis C Virus Genotype Distribution among HIV-1 Infected People from Various High-risk Groups

Di Tian, Xiaoyuan Xu
Departments of Infectious Diseases, Peking University First Hospital, Beijing, China

Background: Since the introduction of highly active antiretroviral therapy (HAART), the survival rate in HIV/HCV co-infected people has significantly improved and HCV-induced liver diseases have emerged as the most important co-morbidities. Coinfection heightens the risk of HAART-related hepatotoxicity. Thus, all co-infected individuals should be considered for HCV infection screening. The aim of our study was to investigate the prevalence of HCV antibodies (anti-HCV), the proportion of HCV RNA positive individuals, and the subtype diversity of HCV genotypes in HIV-1 infected people from various high-risk groups. Methods: A total of 1, 112 HlV-1 positive individuals were recruited from various risk routes in Henan and Guangxi and then tested for anti-HCV. All the samples were subjected to PCR amplification for 5'NCR/C region, C/E2 region and NS5B region. The subtype characterization of HCV was determined by phylogenetic analysis. Results: The overall seroprevalence rate of HCV in HIV-infected subjects was 26. 9% (299/1, 112). The highest prevalence of HIV/HCV co-infection was observed in former blood donors (FBDs) (87. 2%), followed by intravenous drug users (IDUs) (82. 1%). HCV RNA was detected in 209 (18. 8%) samples. 110 (36. 8%) anti-HCV positive samples were negative for HCV RNA. The negative rate for HCV PCR amplification in anti-HCV positive patients was high in patients who acquired HIV-infection through perinatal exposure or transfusion (66. 7% and 63. 2%, respectively) and low in IDUs (20. 0%). In contrast, 20 (2. 5%) anti-HCV negative samples were positive for HCV RNA. Nine HCV subtypes 1a, 1b, 2a, 3a, 3b, 6a, 6e, 6n and 6u were detected in this study, showing a complex HCV epidemic. In Henan, the most prevanlent HCV subtype was 1b (52. 7%), followed by subtype 2a (41. 9%). Subtypes 1a, 3a and 6n were prevalent only in patients with sexual contact. Subtype 6a (35. 6%) was the most prevalent, and subtypes 3b (32. 9%) was the second most prevalent genotypes in Guangxi. Subtypes 6e and 6n were prevalent only in IDUs, subtypes 1a, 1b and 6a were prevalent not only in IDUs, but also in the patients with sexual contact. Subtype 3a was not detected in IDUs. Subtypes 6a and 3b were absent from people with sexual contact in Henan, but they accounted for 35. 3% and 23. 5% of HCV infection in Guangxi, respectively. Conclusions: The seroprevalence rate of HCV was significantly higher in HIV-infected people than in general populations. HCV genotype distribution is not only associated with the transmission route, but also associated with the geographic region.


The following people have nothing to disclose: Di Tian, Xiaoyuan Xu


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HCV Transmission among Young IDUs in New York City: The Swan Project

Brian R. Edlin1,2, Emily R. Winkelstein1, 2, Marla A. Shu2,3, Michael R. Carden2, 4, Courtney McKnight3, Heidi Bramson3, Srikanth Goli1,Michael P Busch5,6, Leslie H. Tobler5, Barbara Rehermann7, Don C. Des jarlais3, Ann B. Beeder2
1Institute for Infectious Diseases, National Development and Research Institutes, New York, NY; 2Center for the Study of Hepatitis C and Department of Public Health, Weill Cornell Medical College, New York, NY; 3Beth Israel Medical Center, New York, NY; 4Deceased, New York, NY; 5Blood Systems Research Institute, San Francisco, CA; 6University of California' San Francisco, CA; 7Liver Diseases Branch, National Institutes of Health, Bethesda, MD

Background: HCV transmission continues even in locations where people who inject drugs (PWlDs) have access to sterile syringes. Methods: We recruited PWIDs in New York during 2005 2012 who were young (1 8-35 years) or had injected drugs < 5 years. Those testing HCV negative were offered enrollment in a prospective cohort in which they underwent biweekly risk behavior interviews and HCV RNA testing. Results: Of 714 eligible participants, 371(52%) tested HCV negative; of these, 224 (60%) were followed prospectively for a mean of 192 days. Of these, 209 (93%) were white, 153 (68%) were men, and 130 (58%) were homeless. During person-years of follow-up, 26 became infected (incidence, 22. 4/100 person-years (%/yr)). HCV incidence during the period immediately preceding enrollment, calculated using data on participants in the window period on enrollment (23 [6. 1%] of 379 HCV seronegatives were HCV RNA positive), was even higher (43. 5%/yr). Acquiring HCV was strongly associated with younger age (35. 8%/yr, 18-21 years; 29. 6%/yr, 22-25 years; 17. 9%/yr, 26-29 years; 0. 0%/yr, >30 years; p=0. 001), shorter duration of injection drug use (78. 6%/yr, <6 months; 34. 7%/yr, 1 year; 21. 8%/yr, 2-9 years; 4. 2%/yr, >10 years; p=0. 006), shorter duration of study participation (49. 9%/yr, first 60 days; 20. 3%/yr, next 60 days; 10. 2%/yr, >120 days; p=0. 005), drug sharing (32. 6%/yr vs. 14. 1%/yr, relative hazard [RH]=2. 7, p=0. 02), dividing drugs with a used syringe (89. 4%/yr vs. 18. 3%/yr, RH=5. 1, p=0. 001) syringe sharing (51. 2%/yr vs. 17. 9%/yr, RH=3. 9, p=0. 004), and cooker sharing (57. 4%/yr vs. 13. 3%/yr, RH=5. 2, p<0. 001). Nonmonogamous sharing was associated with greater risks than monogamous sharing, but incidence was 14. 9%/yr even when participants reported not sharing drugs or injection equipment at all. Methadone maintenance was associated with decreased risk (4. 5%/yr vs. 33. 6%/yr, RH=0. 13, p=0. 006). Injecting in public locations was associated with increased risk (none, 0%/yr; some, 16. 8%/yr; most, 35. 3%/yr; p=0. 01). Conclusion: HCV incidence is extraordinarily high among PWIDs, especially those who are young, started injecting recently, or have riskier injection practices. Incidence decreased the longer participants remained in the study. Methadone maintenance and safe injection locations may decrease transmission. HCV antibody and RNA testing in high-risk populations can identify individuals in the earliest stages of infection. Funding: NIH (R01-DA03574, R01-DA16159, R01-DA021550, M01-RR000047, UL1RR024996). No industry funding or conflicts.


The following people have nothing to disclose: Brian R. Edlin, Emily R. Winkelstein, Marla A. Shu, Michael R. Carden, Courtney McKnight, Heidi Bramson, Srikanth Goli, Michael P. Busch, Leslie H. Tobler, Barbara Rehermann, Don C. Des Jarlais, Ann B. Beeder


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Trends in hospital utilization among chronic hepatitis C patients in the US; the Chronic Hepatitis Cohort Study (CHeCS) 2006-2010

Eyasu H. Teshale1,Jian Xing1,Anne C. Moorman1, Loralee B. Rupp2, Stuart C. Gordon2, Joseph A. Boscarino5, Mark A. Schmidt3, Vinutha Vijayadeva4, Philip R. Spradling1,Scott D. Holmberg1, Fujie Xu1
1Center for Disease Control and Prevention, Atlanta, GA; 2Henry Ford Health System, Detroit, MI; 3The Center for Health Research, Kaiser Permanente Northwest, Portland, OR; 4Kaiser Permanente, Hawaii, Honolulu, HI; 5Geisinger Health Systems, Danville, PA

Background: Patients with chronic hepatitis C (CHC) and cirrhosis (CHC-C) are at risk of developing episodes of decompensation that require hospitalizations. In this analysis we determine trends in hospital utilization by site, age, gender, and among persons with presumed CHC-C in the US. Methods: We analyzed data from CHC patients who received care at CHeCS sites from 2006-2010. CHeCS is an observational cohort of chronic viral hepatitis in the United States at four integrated health care systems designed to assess natural history and clinical outcomes in demographically diverse settings. Hospital utilization, in days/person-year, was calculated by dividing the total length of acute care hospital stay in days each year by the average number of CHC patients in that year. We utilized Fib-4 score >5. 88, which has previously been shown in this population to have a specificity of 98% and PPV of 83% for cirrhosis, as an indicator of cirrhosis. Results: Among 10, 998 patients with CHC, 4, 600 (41. 8%) were hospitalized at least once during 2006-2010. Among hospitalized cases: 87. 8% were >45 years of age, 60. 5% were male, 54. 2% were white, and 26. 6% had a Fib-4 score >5. 88 at hospitalization. Among those hospitalized that had a Fib-4 score >5. 88 at hospitalization: 96. 1% were >45 years of age, 66. 4% were male, 56. 1% were white, and 25. 9% were black. Overall, hospital utilization increased from 2. 5 days/person-year in 2006 to 3. 0 days/person-year in 2010. Utilization varied by age from 1. 83 days/person-year among persons in the age group 18-29 years to 2. 89 days/person-year among persons 60 years of age and older. In 2010, hospital utilization by persons 60 years of age and older was 3. 64 days/person-year; an increase of 57% from 2006. In the same year hospital utilization varied by gender with 3. 23 days/person-year vs. 2. 57 days/person-year for male and female, respectively. During 2005 2010, hospitalization days for persons with CHC-C increased by 107% from 4. 2 days/person-year to 8. 7 days/person-year (p=0. 02). Conclusion: In this cohort of CHC patients under medical care, hospital utilization was higher among males, persons older than 60 years of age; this utilization increased from 2006-2010 overall, and especially so among persons with presumed CHC-C. Higher levels of hospital utilization among patients with more advanced disease may reflect an emerging phenomenon that requires additional investigation to determine underlying causative factors.


Stuart C. Gordon - Advisory Committees or Review Panels: Tibotec; Consulting: Merck, CVS Caremark, Gilead Sciences, BMS; Grant/Research Support: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS, Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc.

The following people have nothing to disclose: Eyasu H. Teshale, Jian Xing, Anne C. Moorman, Loralee B. Rupp, Joseph A. Boscarino, Mark A. Schmidt, Vinutha Vijayadeva, Philip R. Spradling, Scott D. Holmberg, Fujie Xu


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Management of mental illness and substance use prehepatitis C therapy: Expanding patient access and improving outcomes

Kimberly Corace1,2, Gary Garber1,3,Mark Kaluzienski1, Glen T. Howell4, Christina Vaz1,2, Craig Lee1,2, Thomas Shaw-Stiffel1,2, Louise Balfour1,2, Curtis Cooper1,2
1University of Ottawa at The Ottawa Hospital, Ottawa, ON, Canada; 2Ottawa Hospital Research Institute, Ottawa, ON, Canada; 3Public Health Ontario, Ottawa, ON, Canada; 4Carleton University, Ottawa, ON, Canada

Background: Mental illness, substance use, and psychosocial issues remain key barriers to hepatitis C (HCV) treatment. Despite treatment advances with direct-acting antivirals (DAA), patients with mental health and substance use co-morbidities may not realize the significant benefit of these medications. Our multidisciplinary viral hepatitis clinic includes psychosocial support (i. e., psychology, psychiatry, and social work), with the goal of improving patients' HCV treatment readiness, adherence, and success. Objectives: To evaluate the (1)impact of multidisciplinary care on HCV treatment outcomes among patients with mental health and substance use disorders, and (2) time required to prepare patients with these disorders for treatment. Methods: HCV RNA+ patients were recruited during their initial visit at a large Canadian hospital-based viral hepatitis clinic. Patients completed measures of sociodemographics, mental health, substance use, and psychosocial barriers to care on their initial clinic visit and at multiple time points thereafter. Information on HCV treatment initiation and outcomes were collected via medical chart review and a clinical database. Results: Of the total sample (N=436; 69% male; 75% Genotype 1), 67% reported drug use history, 35% had a drug problem warranting intensive treatment, and 29% engaged in harmful drinking. Pre-treatment, 49% were depressed, 28% had anxiety, 15% bipolar disorder, and 20% were previously hospitalized for mental illness. Patients with baseline mental health and substance use issues took longer to initiate HCV antiviral treatment (p<. 05). For example, those with anxiety disorders took 1. 5 times longer (F=5. 04, p<. 05, n2=. 03) and those on methadone took 2. 8 times longer to start treatment (F=10. 27, p<. 01, n2=. 08). Treatment start was delayed due to higher use of psychiatric/psychological services (p<. 05). Of patients who started treatment, 70% successfully completed treatment; 30% prematurely discontinued, primarily due to virological failure and physical adverse events. Only 2% discontinued due to psychological side-effects. Chi-square analyses indicated patients with mental health and substance use disorders at baseline achieved similar SVR rates as those without these conditions (p>. 05). Conclusions: HCV patients with mental health and substance use disorders take longer to initiate HCV treatment. However, within a multidisciplinary team they can successfully access and complete treatment with outcomes comparable to patients without these co-morbidities. Managing these co-morbidities pre-HCV treatment takes time, but may enable more patients to successfully initiate and complete DAA therapy.


Kimberly Corace - Grant/Research Support: pfizer Gary Garber - Grant/Research Support: pfizer

Mark Kaluzienski - Advisory Committees or Review Panels: Lundbeck, Jannsen; Speaking and Teaching: Bristol-Myers Squibb, Jannsen, Astra Zeneca, Pfizer

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche,

The following people have nothing to disclose: Glen T. Howell, Christina Vaz, Craig Lee, Thomas Shaw-Stiffel, Louise Balfour


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Genetic Variants in the Apoptosis Gene, BCL-XL, Improve Sustained Virological Response to Interferonbased Treatment of Chronic Hepatitis C genotype 1

Louise N. Clausen1, Nina Weis1, Steen Ladelund1, Lone W. Madsen2, Suzanne Lunding3, Britta Tarp4, Peer B. Christensen5, Henrik Krarup6, Axel Møller7, Jan Gersfoff8, Mette Clausen8, Thomas Benfield1
1Copenhagen University Hospital, Hvidovre, Denmark; 2Køge Hospital, Køge, Denmark; 3Hillerød Hospital, Hillerød, Denmark; 4Silkeborg Regional Hospital, Silkeborg, Denmark; 5Odense University Hospital, Odense, Denmark; 6Aalborg University Hospital, Aalborg, Denmark; 7Kolding Regional Hospital, Kolding, Denmark; 8Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Aim. Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on response to HCV treatment with pegylated interferon-α and ribavirin (pegIFN/RBV). Methods. A candidate gene association study in a prospective cohort of 220 chronic HCV infected individuals undergoing treatment with pegIFN/RBV. Differences between individuals were compared in multivariate logistic regression adjusted for age, HCV viral load (VL) and interleukin 28B (IL28B) genotypes. We constructed receiver operating characteristics (ROC) curves. Results. Eight single nucleotide polymorphisms (SNPs) were significantly associated with sustained virological response (SVR); all 8 were in the B-cell lymphoma extra large (BCL-XL) gene and in complete linkage disequilibrium (R square =1). In multivariate regression, the favourable BCL-XL genotype was associated with SVR with an adjusted odds ratio (aOR) ranging from 2 一 13 for HCV genotypes 3 and 1, (((1: a〇R, 12. 9; (95% confidence interval (Cl), 2. 1, 150. 8); p = 0. 002), 3: aOR, 3. 1; (95% Cl, 0. 5, infinity); p = 0. 3)); respectively. Analysis of ROC curves revealed an increased area under the curve (AUC) when amending BCL-XL (AUC, 0. 78 (95% Cl, 0. 68, 0. 87)) to the combined curve of age, HCV VL and IL28B genotype (AUC, 0. 69 (95% Cl, 0. 58, 0. 80)), (p = 0. 01) for HCV genotype 1. Conclusion. We identified anti-apoptotic SNPs in the BCL-XL gene associated with SVR to HCV treatment and which, in combination with IL28B, significantly improved the prediction of SVR for HCV genotype 1 Additionally studies are warranted to investigate whether BCL-XL may influence SVR to therapy involving direct acting antivirals or even interferon-free regimens.


Nina Weis - Advisory Committees or Review Panels: Bristol-Myers Squibb, Glaxo Smith Kline, Gilead, Janssen, Merck Sharp Dohme; Grant/Research Support: The Dansih Council for Independent Research; Medical Sciences; Speaking and Teaching: Janssen

Jan Gerstoft - Advisory Committees or Review Panels: msd, medivir, gilead; Speaking and Teaching: msd, abbivie, bms, viiv, gilead

The following people have nothing to disclose: Louise N. Clausen, Steen Ladelund, Lone W. Madsen, Suzanne Lunding, Britta Tarp, Peer B. Christensen, Henrik Krarup, Axel M0ller, Mette Clausen, Thomas Benfield


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Screening for alcohol abuse using the CAGE questionnaire in patients with hepatitis C: association with cirrhosis and alcohol abuse/dependence

Luciana D. Silva1, 2, Elson C. Velanes Neto2, Eduardo P. de Carvalho2, Graziela C. Nascimento2, Gabriela S. Duarte2, Luciana R. da Cunha2, Rosangela Teixeira1, 2, Fernando S. Neves3
1Department of Internal Medicine, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Belo Horizonte, Brazil; 2Ambulatory of Viral Hepatitis, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Belo Horizonte, Brazil; 3Department of Mental Health, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Belo Horizonte, Brazil

Background and aims: A significant proportion of hepatitis C virus (HCV) chronically infected patients will develop liver cirrhosis and its potential complications: impaired liver function, portal hypertension or hepatocellular carcinoma. The natural history of HCV infection is determined by both genetic and environmental factors. Among these, alcohol abuse is a relevant environmental risk factor and it is independently associated with reduced HCV clearance and accelerated liver disease course. In this study, we evaluate past and current alcohol consumption in terms of amount, frequency and duration of use in patients with chronic hepatitis C (CHC) and healthy individuals (blood donors). Additionally, we examine the relationship between positive CAGE screen (defined as two or more affirmative answers) and severity of liver disease and alcohol abuse/dependence. Methods: 150 consecutive CHC patients and 110 healthy individuals were prospectively enrolled. All individuals completed several surveys including Mini-lnternational Neuropsychiatry Interview (MINI-Plus 5. 0) and CAGE questionnaire. Clinical, laboratory and sociodemographic variables were evaluated in CHC patients and control group with and without positive CAGE screen, respectively. Psychiatric comorbidities were diagnosed according to DSM-IV criteria. The data were evaluated using logistic models. Results: Characteristics of patients with CHC vs. control group were: male (42. 4% vs. 48. 6%, p=0. 34); age/years (53. 2 ± 11. 6 vs. 36. 0 ± 7. 8, p<0. 001). Prevalence of positive CAGE screen was 24. 2% vs. 14. 7% (p=0. 06) in patients with CHC vs. controls. Alcohol abuse/dependence was 22. 3% vs. 3. 7% in patients with CHC vs. control group (p<0. 0001). Presence of cirrhosis was associated with positive CAGE screen (OR: 3. 09; 95%CI 1. 12-8. 57, p=0. 03), duration of alcohol use/years [33. 1 ± (cirrhotic patients) vs. 20. 8 ± 15. 2 (non-cirrhotic patients); p=0. 002] and frequency of alcohol use (> 3 times/week vs. < times/week, p=0. 04). In multivariate analysis, adjusted for sex, age and income, positive CAGE screen was associated with current and past alcohol abuse/dependence(OR: 8. 13; 95%CI 3. 73-17. 71, p<0. 001). 〇ur study suggests that the CAGE questionnaire is a relevant instrument to evaluate drinking problems in CHC patients. Furthermore, positive CAGE screen was associated with cirrhosis in this population. Alcohol consumption should be investigated in HCV-infected patients, particularly based on the deleterious effect of alcohol in the course of liver disease. PROEX, PRPq, CAPEs, CNPq


The following people have nothing to disclose: Luciana D. Silva, Elson C. Velanes Neto, Eduardo P. de Carvalho, Graziela C. Nascimento, Gabriela S. Duarte, Luciana R. da Cunha, Rosangela Teixeira, Fernando S. Neves


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Relationship of Insulin Resistance and IL28B Gene Polymorphism in Chronic Hepatitis C Patients

Ying Liu1, Cheng Hu2, Zhi-xing Zhao1
1Department of Infectious disease, The 3rd Affliated Hospital of Sun Yat-sen Univeristy, Guangzhou, China; 2Department of Urology, The 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

Purpose: Recent research revealed that both IL28B gene polymorphism and insulin resistance are predictors in the treatment of chronic hepatitis C (CHC) by the combination of Pegylated interferon with Ribavirin. Current study was aimed for identifying the relationship of insulin resistance and IL28B gene polymorphism in CHC patients. Methods: Serum samples of 262 CHC patients were collected, IL28B gene SNP (rs12979860) as well as other clinical indicators were compared retrospectively, including hemeostasis model assement of insulin resistance (HOMA-IR), aspartate aminotransferase (AST), alanine aminotransferase (ALT), y-glutamyl (GGT), total bilirubin (TB), hepatitis C RNA viral load, glycosylated hemoglobin, fasting glucose and fasting insulin. Results: HOMA-IR in CHC patients with C/T allele was significantly higher than that in pure CC type patients (5. 150 ±0. 7751vs. 3. 821 ±0. 2854, p<0. 05). IL28B SNP(rs12979860) TT type in CHC patients with insulin resistance was higher that whose without insulin resistance(71. 3% vs. 41. 4%, p<0. 05). Liver function indicators, blood triglycerides, hepatitis C RNA viral load and fasting glucose were similar in rs12979860 SNP TT type and TG/GG type (p>0. 05). Multiple regression analysis revealed that SNP (rs12979860) T allele is an independent risk factor for CHC patient develops into insulin resistance. Conclusion: We propose CHC patients with IL-28B SNP (rs12979860) of C/T allele is more straightforward to emerge with insulin resistance than CC type. Key Words: chronic hepatitis C, insulin resistance, IL28B, gene polymorphism


The following people have nothing to disclose: Ying Liu, Cheng Hu, Zhi-xing Zhao


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Predictors of Sustained Virologic Response (SVR) in chronic hepatitis C patients in the Era of current Direct Acting Agents

Omar Mousa2, Chang H. Kim3, Ly-Elaine Pham4, Chukwuma I. Egwim1, Scott A. Zela1, Victor Ankoma-Sey1
1Hepatology, Liver Associates of Texas, Houston, TX; 2Internal Medicine, State University of New York - Upstate Medical University, Syracuse, NY; 3School of Medicine, State University of New York - Upstate Medical University, Syracuse, NY; 4School of Medicine, University of Texas Health Science Center, San Antonio, TX

Background/Aim: Predictive factors associated with SVR following treatment with peginterferon and Ribavirin (P/R) in chronic hepatitis C patients (CHC) is well established. However, there is limited data available to date to predict a response to currently available NS3/4A protease inhibitors; Telaprevir (TVR) and Boceprevir (BVR). Methods: CHC patients consented to join our prospective cohort as they received therapy with TVR or BVR as part of the response guided triple therapy. Futility rules were strictly applied while following patients between July 2011 and May 2013. Endpoints of the study included identification of significant predictive factors to end of treatment response (ETR), SVR for 12 weeks (SVR12), and SVR for 24 weeks (SVR24). Statistical software package R (version 2. 10. 1, R Foundation for Statistical Computing) was used for all analysis. Correlation matrices were built to identify any differences between the TVR and BVR groups in maintenance of treatment response at weeks 4, 12, and 24 as well as ETR, SVR12 and SVR24. Fisher's z-transform method was used for significance testing between correlations. Logistic regression models for treatment response at ETR, SVR12, and SVR24 were built. Significance testing for each predictor was based on the z-statistic. Results: 113 CHC patients (Female 52. 9%, mean age 54. 5 (SD 8.1), mean BMI 30. 2 Kg/m2 (SD 6. 51)) were enrolled. 107 who reached the end of treatment were analyzed. Predictor variables included extended rapid virologic response, pre-treatment category, genotype, race, gender, age and BMI. For the logistic regression models at ETR, SVR12 and SVR24, achieving an eRVR was a statistically significant predictor for treatment response. Based on the odds ratios, eRVR was the predominant positive predictor of treatment response as follows: at ETR (OR: 13. 40), SVR12 (OR: 11. 08) and at SVR24 (OR: 11. 32). Interestingly, BVR was found to be significantly better than TVR in maintenance of treatment response between weeks 4, 12, and 24, based on the correlation matrices (p<0. 01). Conclusion: Based on our models, eRVR can be identified as a statistically significant predictor of ETR, SVR12, and SVR24. Future studies with larger sample sizes may reveal other predictors of response that can influence the DAA selection in CHC triple therapy.

Table 1: eRVR as a positive predictor of treatment response to DAAs.

Response to DAAseRVR
Odds RatioP-value
ETR13. 400. 000092
SVR 1211. 080. 00033
SVR2411. 320. 00114


Chukwuma I. Egwim - Advisory Committees or Review Panels: Bristol Myers Squibb, Gilead; Speaking and Teaching: Onyx Pharmaceuticals, Gilead

Scott A. Zela - Advisory Committees or Review Panels: Gilead; Speaking and Teaching: Merck, Vertex

Victor Ankoma-Sey - Advisory Committees or Review Panels: Salix, Genentech, Merck, Vertex, BMS; Grant/Research Support: Gilead sciences, Novartis, BMS, J&J, Abbott; Speaking and Teaching: Salix, Genentech, Merck, Vertex, BMS

The following people have nothing to disclose: Omar Mousa, Chang H. Kim, LyElaine Pham


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Comorbidity, Healthcare Resource Use (HRU), Productivity, and Quality of Life (QOL) Burden in Hepatitis C (HEP C): Results from a 2012 U. S. Health Survey

J. B. Forlenza1, K. Annunziata2, Neeta Tandon1
1Janssen Scientific Affairs, LLC, Titusville, NJ; 2Kantar Health, Princeton, NJ

Purpose: To evaluate characteristics, HRU, productivity, and QOL in individuals with Hep C compared to those without Hep AMethods: Individuals who self-reported a Hep C diagnosis (Hep C group) and those without Hep C (Non-Hep C group) were identified from the 2012 U. S. National Health and Wellness Survey (NHWS)—an annual, cross-sectional, self-administered, internet-based survey of persons aged >18 years. The 7 NHWS was Essex IRB approved, and respondents provided informed consent. Bivariate analyses evaluated group differences for self-reported productivity, QOL (SF-36v2), past 6-month HRU, and select medical conditions. There was no matching between groups. Results: There were 675 individuals with a Hep C diagnosis (mean time since diagnosis=15. 6 years). The Hep C group was older (54. 0 vs. 48. 6 years, p<0. 05) and had less college graduates (25. 9% vs. 40. 2%, p<0. 05) than the Non-Hep C group (n=70, 460). The Hep C group was comprised of proportionately more males (69. 8% vs. 48. 6%), non-Whites (31. 6% vs. 27. 6%), household incomes <$25, 000 (36. 0% vs. 19. 2%), uninsured (22. 2% vs. 18. 2%), and obese/overweight (body mass index >25 m/kg2) respondents (71. 0% vs. 65. 8%) versus the Non-Hep C group, respectively; all p-values <0. 05. A diagnosis of anemia, hepatitis B, HIV/AIDS, cancer, diabetes, moderate/severe kidney disease, cirrhosis, chronic liver disease, anxiety, and depression was reported by proportionately more in the Hep C group versus those without Hep C (all p-values <0. 05). The Hep C group had a higher proportion visiting ERs (24. 1%), hospitals (15. 6%), and family/general practitioners (61. 0%) in the past 6 months versus the Non-Hep C group (1l. 0%, 6. 5%, and 49. 5%, respectively; all p-values <0. 05). Nearly half of all insured Hep C individuals (vs. 39. 1% Non-Hep C) needed referrals for specialists, while 67. 8% of those without Hep C (vs. 56. 0% Hep C) had copays for doctors' visits (p<0. 05 for both). Approximately 43. 7% of the Hep C group was employed (full or parttime/self/short-term disability) versus 53. 6% of the Non-Hep C group (p<0. 05). As compared to those without Hep C, Hep Cdiagnosed individuals had significantly higher levels of absenteeism, presenteeism, overall work impairment, and activity impairment and significantly lower QOL scores on each of the SF-36 domains measured as well as for the SF-36 Physical and Mental Component Summary scores (all p-values <0. 05; data not shown). Conclusions: Individuals diagnosed with Hep C reported more comorbidity burden and higher use of healthcare services than those without Hep C as well as worse productivity and QOL. These results further demonstrate the current burden of Hep C in the U. S.


J. B. Forlenza - Employment: Janssen Scientific Affairs, LLC; Stock Shareholder: Janssen Scientific Affairs, LLC

K. Annunziata - Employment: Kantar Health

Neeta Tandon - Employment: Johnson & Johnson Co


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Hepatitis C Prevalence in Asian Patients With Hepatocellular Carcinoma: a systematic review and meta-analysis

Wei Zhang, Huiying Rao, Feng Liu, Bo Feng, Lai Wei
Peking University People's Hospital,Hepatology Institute, Beijing, China

Background: Most cases of hepatocellular carcinoma (HCC) are associated with chronic hepatitis C (CHC) infection. CHC and HCC are underappreciated health problems in many Asian countries and in the US, where Asians is one of the fastest growing immigrant groups in USA. However, the prevalence of CHC in Asian patients with HCC has not been described before. The objective of this systematic review and meta-analysis on published observational studies is to estimate the exact incidence of CHC in Asian patients with HCC. Methodology: We identified eligible studies by searching the relevant databases, including PubMed, Embase, and CNKI. The selection of eligible papers was carried out using a scoring system based on guidelines and inclusion criteria that were established before the articles were identified. Heterogeneity across studies was determined and the meta-analysis was performed following standard guidelines. Results: 31 cohort studies involving 7305 Asian patients were included in the meta-analysis. The pooled prevalence estimates for hepatitis C antibody in Asian patients with HCC was 21. 8% (95% CI: 16. 0% - 29. 0%)(Fig1). However, there was the low heterogeneity (p <0. 10 and I2 =48. 9%). The geographic location and the length of follow-up were considered potentially important sources of between-study heterogeneity. The pooled prevalence of CHC in HCC patients in China (9%, 95% CI: 6. 2% −12. 9%) was lower than in AsianAmericans (27. 1%, 95% CI: 21. 4% - 33. 7%) Conclusions: Data suggest a moderate to high prevalence of hepatitis C in HCC patients in different areas of Asia. It advocates the screening for HCV infection in Asia. It may be useful in estimation of the burden of the disease in Asian.


Lai Wei - Consulting: Gilead; Grant/Research Support: BMS, Roche, Novartis; Speaking and Teaching: Gilead

The following people have nothing to disclose: Wei Zhang, Huiying Rao, Feng Liu, Bo Feng


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Strategies for assigning HIV/hepatitis C virus genotype 1 coinfected patients to dual-therapy or triple-therapy

Mattias Mandorfer1, Thomas Reiberger1, Berit A. Payer1, Karin Neukam2, Antonio Rivero3, Massimo Puoti4, Christoph Boesecke5, Axel Baumgarten6, Anna Grzeszczuk7, Robert Zangerle8, Dirk Meyer-Olson9, Jurgen K. Rockstroh5, Michael Trauner1, Juan A. Pineda2, Markus Peck-Radosavljevic1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 2Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain; 3Department of Infectious Diseases, Hospital Universitario Reina Sofίa, Córdoba, Spain; 4Department of Infectious Diseases, AO Ospedale Niguarda Ca' Granda, Milano, Italy; 5Department of Internal Medicine I, University of Bonn, Bonn, Germany; 6Praxis Driesener Strasze, Berlin, Germany; 7Department of Infectious Diseases and Hepatology Medical University of Bialystok, Bialystok, Poland; 8Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria; 9Department of Clinical Immunology and Rheumatology, Medical University Hannover, Hannover, Germany

Objective To evaluate strategies for assigning HIV/hepatitis C virus genotype 1 coinfected patients (HIV/HCV-GT1) to either dual-therapy or triple-therapy based on baseline and on-treatment predictors of sustained virologic response (SVR) such as interleukin 28B rs12979860 SNP (IL28B), advanced liver fibrosis, RVR, or a combination of these predictors. Methods 148 HlV/HCV-GT1 who received antiviral therapy with PEGIFN+RBV were included in this multinational, retrospective analysis. Patients with rapid virologic response (RVR) were treated for 48 weeks, while patients without RVR had either 48 or 72 weeks of treatment duration. Advanced liver fibrosis was defined as either METAVIR F3/F4 or liver stiffness >9. 5kPa. Patients were divided into groups according to their IL28B and liver fibrosis status: high probability of SVR (hSVR: IL28B C/C and no advanced liver fibrosis); medium probability of SVR (mSVR: either IL28B non-C/C or advanced liver fibrosis and low probability of SVR (lSVR: IL28B non-C/C and advanced liver fibrosis). Results RVR and sustained virologic response (SVR) were observed in 26% (39/148) and 57% (84/148) of patients, respectively. A trend toward higher SVR rates in patients with IL28B C/C (65%; 37/57) when compared to patients with IL28B non-C/C (51 %; 40/79; p=0. 097) was observed. Higher SVR rates were observed in patients without advanced liver fibrosis(61 %(47/77) vs. 42%(22/52); p=0. 036) and in patients with RVR (90%(35/39) vs. 45%(49/109); p<0. 001). The corresponding positive (PPV) and negative predictive values (NPV) were: IL28B C/C: PPV 65%, NPV 49%; No advanced liver fibrosis: PPV 61%, NPV 58%; RVR: PPV 90%, NPV 55%. While the rate of SVR observed in hSVR (70%; 23/33) was comparable to mSVR (56%; 33/59; p=0. 194), patients with lSVR (32%; 9/28) displayed significantly lower SVR rates when compared to both patients with hSVR (p=0. 003) and mSVR (p=0. 038). The PPV and NPV of hSVR for SVR were 70% and 52%, respectively. In patients without RVR, significantly higher rates of SVR were observed in patients treated for W72 (62%; 23/37), when compared to patients treated for W48 (36%; 26/72; p=0. 01). Conclusions RVR had an excellent positive predictive value for the response to dual-therapy in HIV/HCV-GT1. Thus, the use of a lead-in phase may be emphasized in order to assign HIV/HCV-GT1 to either dual-therapy or triple-therapy. Alternatively, hSVR criteria may be used to identify patients with a high probability of SVR to dual-therapy without the use of a lead-in phase. However, the necessity of an extension of treatment duration to 72 weeks in HIV/HCV-GT1 without RVR should be strongly considered if triple-therapy is not available.


Mattias Mandorfer - Advisory Committees or Review Panels: Janssen

Thomas Reiberger - Grant/Research Support: Gilead, Gilead, Phenex; Speaking and Teaching: Roche, MSD, Roche, MSD

Massimo Puoti - Advisory Committees or Review Panels: GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis, GSK, Abbott, Janssen, MSD, Roche, Gilead Sciences, Novartis; Speaking and Teaching: BMS, BMS, BMS, BMS

Christoph Boesecke - Speaking and Teaching: MSD, Boehringer, Gilead, BMS, Roche, Abbott

Anna Grzeszczuk - Advisory Committees or Review Panels: Gilead, BMS, GSK; Speaking and Teaching: Abbott

Jurgen K. Rockstroh - Advisory Committees or Review Panels: Abbvie, BI, BMS, Merck, Roche, Tibotec, Abbvie, Bionor, Tobira, ViiV, Gilead, Janssen; Consulting: Novartis; Grant/Research Support: Merck; Speaking and Teaching: Abbott, BI, BMS, Merck, Roche, Tibotec, Gilead, Janssen, ViiV

Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen; Consulting: Falk Pharma, Phenex, Amgen; Grant/Research Support: Intercept; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching: Falk Foundation, Roche, Gilead

Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gilead, Janssen, BMS; Consulting: Bayer, Boehringer-Ingelheim, Jennerex, Eli Lilly; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly

The following people have nothing to disclose: Berit A. Payer, Karin Neukam, Antonio Rivero, Axel Baumgarten, Robert Zangerle, Dirk Meyer-Olson, Juan A. Pineda


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Potential of and first experience with the use of tripletherapy in HIV/hepatitis C virus coinfected patients

Maffias Mandorfer1, Thomas Reiberger1, Berit A. Payer1, Maximilian C. Aichelburg2, Florian Breitenecker2, Gerold Lang2, Armin Rieger2, Michael Trauner2, Markus Peck-Radosavljevic2
1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 2Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria

Objective To assess the potential of and to report our first experience with the use of triple-therapy with boceprevir (BOC) and telaprevir (TPV) in the treatment of hepatitis C virus coinfection in HIV-positive patients (HIV/HCV). Methods 443 HIV-positive patients with positive HCV serology diagnosed at the Medical University of Vienna after 2005 were included in this retrospective analysis. Results 290 of 443 HCV/HIV patients had a treatment visit at the Medical University of Vienna in 2012 or later. Data on HCV-RNA levels were available in 237 of these 290 patients. 54% (128/237) of patients had detectable HCVRNA and 75 of these patients (59%) had HCV-genotype (HCVGT)1. 41% (31/75) of HCV-G十1 coinfected patients displayed at least one contraindication to triple-therapy: n=28 (37%) insufficiently controlled HIV infection, n=1(1%) anemia, n=1 (1%) thrombocytopenia, n=1(1%) leukopenia, and n=2 (3%) decompensated cirrhosis. While the majority of the 44 patients wihtout a contraindication against triple-therapy were treatmentnaive (n=31; 70%), 13 patients (30%) were treatment-experienced. Combined antiretroviral therapy (cART) switch or dose adjustment would have been recommended in 77% (34/44) and 59% (26/44) of HIV/HCV prior to the initiation triple-therapy with BOC and TPV, respectively. Considering SVR rates to triple-therapy in treatmen-naive and treatment-experienced HCV-monoinfected patients, SVR would be expected in 70% (3 1/44) of patients. Thus, triple-therapy might cure HCV-infection in 24% (31/128) of HIV/HCV. 16 HIV/HCV have received triple-therapy until 5-JUN-201 3. 15 HlV/HCV have received BOC, while 1 patient recieved TPV. 60% (6/10) of HIV/HCV on BOC had a RVR, while no RVR was observed in the patient treated with TPV. 2 patients, 1 on BOC and 1 on TPV met the week 12 futility rule and 3 patients had premature treatment disconinuation at week 28 due to exhaustion (n=2), or a muscle abscess (n=1). Of these 3 patients, all had undetectable HCV-RNA 4 weeks after the end of therapy. Add-on of BOC at week 12 has been performed in 3 patients with acute hepatitis C and a poor response to dual-therapy and resulted in undetectable HCV-RNA within 4 weeks. Conclusions Generally, the uptake of triple-therapy in HIV/HCV is often limited by patient noncompliance to scheduled treatment visits, the restriction to HCV-GT1, and insufficiently controlled HIV-infection. The latter may be attributed to poor drug adherence. cART switch or dose adjustments are necessary in the majority of patients. The rates of on-treatment virologic response to triple-therapy were high in both HIV-positive patients with acute and chronic hepatitis C.


Mattias Mandorfer - Advisory Committees or Review Panels: Janssen

Thomas Reiberger - Grant/Research Support: Gilead, Gilead, Phenex; Speaking and Teaching: Roche, MSD, Roche, MSD

Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen; Consulting: Falk Pharma, Phenex, Amgen; Grant/Research Support: Intercept; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching: Falk Foundation, Roche, Gilead

Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gilead, Janssen, BMS; Consulting: Bayer, Boehrinqer-lnqelheim, Jennerex, Eli Lilly; Grant/Research Support: Bayer, Roche, Gilead, MSD; Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly

The following people have nothing to disclose: Berit A. Payer, Maximilian C. Aichelburg, Florian Breitenecker, Gerold Lang, Armin Rieger


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HCV genotype 3a core polymorphism in Indian patients is not associated with hepatic steatosis

Manish C. Choudhary1, Banishree Saha3,Vidhya Natarajan1, Priyanka Pandey Pandey2, Ekta Gupta2, Syed N. Kazim4, Shvetank Sharma1,Shiv K. Sarin1
1Research, Institute of Liver and Biliary Science, New Delhi, India; 2Virology, ILBS, New Delhi, India; 3Medicine, University of Massachusetts Medical School, Worcester, MA; 4Centre for Interdisciplinary Research in Basic Sciences, Jamia Milia University, New Delhi, India

Background: Hepatic steatosis is a common histological feature of Hepatitis C virus (HCV) infection. HCV genotype (GT) 3a core protein is associated with marked accumulation of neutral lipids contained in large lipid droplets compared to GT 1b core protein. However, there is still no consensus on association of HCV core sequence polymorphism and steatosis in HCV GT 3a patients. We aimed at investigating specific polymorphism in HCV GT 3a core protein and its association with increased lipid accumulation in these patients. Method: The study group included patients who were treatment naive, non-alcoholic, HCV GT 3a infected with fibrosis score F=0-2 on liver biopsy. Patients were grouped into non-steatotic (n=17) and steatotic (n=14); moderate to severe steatosis, grade2; 33-67% cells with fat, mild steatosis, grade】; 5-32% cells with fat and no steatosis, grade 0; 0-5% cells with fat. HCV core gene was PCR amplified, cloned and sequenced. Translated HCV core sequences were aligned using ClustalW program in Bioedit, v7. 2. 0 to identify candidate polymorphisms associated with increased intracellular lipid levels. Phylogenetic and molecular evolutionary analyses were conducted with MEGA5 software by maximum likelihood method. For in vitro assessment of lipid accumulation, full length HCV core gene were subcloned in pEGFP-N1 vector and transfected in hepatoma (Huh7) cells and lipid accumulation was assessed by Nile Red staining. Results: We observed 2 polymorphisms at amino acid position 106; domain】;S to N/T (p=0. 45) and 1 62; domain2; I to V (p=0. 47), however, no significant association was found between particular amino-acid residues or motifs in the full genome core region (domains 1, 2 and 3) and steatosis. Residues specific to GT 3a strain, such as F164 were found in all patients irrespective of steatosis severity, as opposed to previous report implicating it with steatosis in vitro. Similarly, phenyla la nine-valine (FV) at positions 1 82 and 1 86 (as opposed to FI) were not found in our study, albeit leucineisoleucine (LI) was found more frequently in both the study groups. Phylogenetic analysis of the core sequences from steatosis and non steatosis patients revealed that sequences were found to be equally distributed throughout the phylogenetic tree. Further, we did not observe a difference in intracellular lipid accumulation in GT 3a core transfected Huh7 cells compared to vector transfected cells. Conclusion: Thus, we conclude that polymorphisms observed in GT 3a core sequence do not associate with steatosis in Indian patients, suggesting the involvement of other HCV proteins or individual host factors in mediating hepatic steatosis.


The following people have nothing to disclose: Manish C. Choudhary, Banishree Saha, Vidhya Natarajan, Priyanka Pandey Pandey, Ekta Gupta, Syed N. Kazim, Shvetank Sharma, Shiv K. Sarin


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Effects of marijuana smoking on hepatitis C infection liver biopsy measures and treatment outcomes

Theresa Liu1, Lucy Turner2, Kimberly Corace1, Gary Garber1, Curtis Cooper1, 2
1Medicine, University of Ottawa, Ottawa, ON, Canada; 2The Ottawa Hospital Research Institute, Ottawa, ON, Canada

Background Marijuana (MJ) use is common in HCV-infected patients. The literature assessing the influence of MJ on liver disease progression and HCV antiviral treatment outcomes is conflicting. Methods We conducted a study of HCV-infected patients followed at The Ottawa Hospital Viral Hepatitis Clinic from 2000-2009. Using The Ottawa Hospital Viral Hepatitis Clinic Database and charts, information was extracted regarding demographics, HIV and HBV co-infection, alcohol use, liver biopsy results, treatment outcomes and self-reported MJ use. Biopsy characteristics and HCV antiviral treatment outcomes were assessed for association with categorized marijuana use by adjusted logistic regression; covariates were specified by clinical relevance a priori. Analyses were conducted using SAS 9. 2. Results Information on MJ use was available for 550 of 1228 (44. 8%) patients: Never Used MJ=325/550 (59. 0%), Active Use=159 (28. 9%), Past Use=66/550 (12. 0%). Of those actively using, 53/159 (33. 3%) regularly smoked> 0. 5 grams/day. Biopsy fibrosis stage and MJ use data was available for 378 (F0-2=72%). Overall, MJ use was not a predictor of fibrosis stage (p = 0. 08). However, regular active MJ users were more likely to have a more severe fibrosis stage (p = 0. 009) compared to participants who have never used MJ by adjusted analysis. Biopsy inflammation grade was available for 377 participants with MJ use data. Overall, increased MJ use predicted increased inflammation grade (p = 0. 0003). Adjusting for injection drug use, alcohol abuse at the time of treatment, sex and race did not influence this result (p = 0. 0002). Biopsy steatosis and MJ use data was available in 359 participants. MJ use was not associated with increased steatosis (p = 0. 55). Genotype predicted steatosis (p = 0. 009). SVR and MJ use data was available for 356 participants of which 203 (57%) achieved an SVR. MJ use was not associated with SVR (p = 0. 70). Conclusion Active MJ use may influence liver fibrosis and inflammation biopsy scores but not steatosis. SVR rates were not increased in active MJ users despite the potential benefit of on-treatment symptom relief.


Kimberly Corace - Grant/Research Support: pfizer Gary Garber - Grant/Research Support: Pfizer

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche,

The following people have nothing to disclose: Theresa Liu, Lucy Turner


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HCV Genetic Diversity and Pre-treatment Frequencies of Protease Inhibitor Resistance-associated Variants (RAVs) in Mono- Versus HCV-HIV Co-infected Patients

Cassandra Jabara3, Fengyu Hu1,Sara Williford1, Prema Menezes1, Corbin Jones3, Michael W Fried1,Joseph J. Eron1, Ronald Swanstrom2, Stanley M. Lemon1
1Dept. of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; 2Dept. of Biochemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC; 3Dept. of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Background and Aims Viral resistance represents a major limitation to the efficacy of direct-acting antiviral agents (DAAs) targeting chronic HCV infection, and arises from the selection of pre-existing resistant variants. Although pre-treatment frequency of resistance-associated variants (RAVs) correlates poorly with response to triple therapy (protease inhibitor + Peg-IFN/RBV), it is likely to have stronger predictive value in IFN-sparing, all DAA combinations. Moreover, pre-treatment RAV frequency may be influenced by immunosuppression accompanying HIV co-infection, a major co-morbidity associated with greater morbidity and mortality in HCV-infected persons. Despite this, the standing genetic variation of in vivo HCV populations remains poorly characterized, particularly in co-infected persons, resulting in potentially misleading estimates of RAV frequency and ignorance of their fate after selection. We addressed this issue by applying ultra high-resolution (<0. 1%) primer-ID sequencing to accurately resolve genetic variation within the NS3 protease domain in 40 HCV treatment-naīve mono- and co-infected subjects. Methods HCV RNA was isolated from the sera of 20 HCV treatment-naīve mono-infected and 20 HIV co-infected individuals on stable HAART with HIV viral load <50c/mL and mean CD4+ cells = 515/mm(3) s. d. =308. cDNA was generated with ID-tagged primers, and re-sequenced using the 454 Junior high throughput platform to produce consensus reads of individual viral RNAs within the region encoding NS3 a. a. 36170. Results Ultra high-resolution primer-ID sequencing accurately resolved thousands of RNA genomes per patient population, directly correcting procedural biases and error. A median sequencing depth of 0. 08% was achieved, far below the platform error rate. Mono-infected viral populations were significantly more diverse (p=0. 013) and contained a higher average RAV frequency than co-infected individuals. Interestingly, measures of HCV population diversity and structure showed a trend between increasing diversity and higher CD4 counts in co-infected patients (Spearman 0. 32-0. 37), although this did not achieve statistical significance (p=0. 11-0. 17 in a two-tailed test). Conclusion In a comparison of 20 mono- and 20 HIV co-infected subjects well-controlled on HAART, coinfected patients demonstrated less pre-treatment genetic diversity and lower RAV frequencies than mono-infected subjects. Differences in pre-treatment RAV frequency do not pose a significant hurdle for success of DAA-based therapies in HIV-HCV co-infected patients.


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

Joseph J. Eron - Consulting: Abbvie

Ronald Swanstrom - Patent Held/Filed: Cellular Research

Stanley M. Lemon - Advisory Committees or Review Panels: Merck, Santaris, Abbott, Gilead; Consulting: Achillion, Idenix; Grant/Research Support: Merck, Tibotec, Scynexis; Speaking and Teaching: Hoffman LaRoche

The following people have nothing to disclose: Cassandra Jabara, Fengyu Hu, Sara Williford, Prema Menezes, Corbin Jones


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Role of Hepatitis E in Decompensation Among Patients With Chronic Hepatitis C

Niharika Samala1, Elizabeth C. Wright2, Vanessa Vargas3, Kirti Shetty4, Rajender Reddy5, Michael R. Lucey6, Harvey J. Alter3, Marc G. Ghany1
1Liver Diseases Branch, National Institute of Dobetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, MD; 2Office of he Director, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, MD; 3Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD; 4Department of Medicine, Medstar Georgetown University Hospital, Washington D. C, DC; 5Department of Medicine, University of Pennsylvania, Philadelphio, PA; 6Department of Medicine, University of Wisconsin, Modison, WI

Background: The factors that cause patients with chronic hepatitis C (CHC) to progress from stable hepatic function to decompensation are poorly understood. Hepatitis E is usually associated with a self-limiting acute hepatitis but can cause acute-on-chronic liver failure in persons with pre-existing liver disease. Aim: To assess whether HEV superinfection contributes to hepatic decompensation in patients with previously stable, but advanced CHC. Methods: A case-control study was performed using stored serum samples from subjects in the HALT-C trial - a multicenter, randomized, controlled study to determine if long-term, low dose peginterferon could prevent disease progression in prior non-responders with advanced CHC. Cases for this study were selected from a group of patients who had clinical outcomes in HALT-C if they developed, over 24 week period, a clinical end point or hepatic decompensation, as indicated by an increase in CTP score by >2, de novo appearance of ascites, hepatic encephalopathy, variceal hemorrhage, spontaneous bacterial peritonitis, need for liver transplant or death. Three controls matched for baseline Ishak fibrosis score, who did not suffer a clinical endpoint by the time of the cases' event were selected for each case. The first available stored sample after decompensation was selected for anti-HEV testing. AntiHEV IgG was tested by ELISA (Wantai, China). Data and serum samples from the HALT-C Trial were provided by the NIDDK Central Repository. Results: 314 out of 1050 patients in the randomized phase of the trial met the HALT-C criteria for a clinical event after a mean follow-up of 3. 5 years. The mean time to event for the 89 selected cases was 2. 2 years. 267 controls matched for baseline fibrosis score and duration to event were selected. Among the cases, the mean age was 51 years, 70% were men, the predominant HCV genotype was 1 and 72% of patients had cirrhosis at baseline. Seroprevalence of anti-HEV in the entire cohort was 21% with no difference in rate between cases (22. 5%) and controls 20. 6%) (p =0. 71). Anti-HEV positivity was associated with older age at baseline (53 years vs 50 years, p=0. 009) but not with other clinical or demographic features. Further testing for anti-HEV on samples from the baseline visit of anti-HEV positive patients is planned to identify incident cases and pinpoint the timing of seroconversion. Conclusion: The sero-prevalence of anti-HEV in the HALT-C cohort was similar to that found in population-based surveys. This preliminary analysis suggests that HEV superinfection might not contribute to hepatic decompensation in patients with CHC and advanced liver disease.


Kirti Shetty - Grant/Research Support: Ikaria, Novartis, Onyx-Bayer, Hyperion; Speaking and Teaching: Merck-Schering Plough, Salix, Gilead, Onyx

Michael R. Lucey - Grant/Research Support: Vertex, Abbvie, Gilead, Salix; Speaking and Teaching: Roche

The following people have nothing to disclose: Niharika Samala, Elizabeth C. Wright, Vanessa Vargas, Rajender Reddy, Harvey J. Alter, Marc G. Ghany


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Health related quality of life scores differ between chronic hepatitis B and C patients? - a case-control study

Carolina L. Goncalves1, Marina C. Loures1, Luciana R. da Cunha1, Claudia C. da Cunha1, Fernando S. Neves1, 3, Rosangela Teixeira1, 2, Luciana D. Silva1, 2
1Ambulatory of Viral Hepatitis-IAG-HCUFMG, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 2Department of Internal Medicine, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; 3Departament of Health mental, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

Background: Several studies have demonstrated that chronic viral hepatitis affects patients' health related quality of life (HRQOL). The reduced overall HRQOL in chronic hepatitis C (CHC) might be better explained by co-occurring conditions, regardless of the stage of the liver disease. However, the effect of the hepatic disease severity on the HRQOL is still controversial. The reports about HRQOL impairment in patients with chronic hepatitis B (CHB) stand scarce. Aims: (1)To investigate whether variables related to the degree of liver impairment, clinical comorbidities, psychiatric illness and sociodemographic characteristics independently affect the HRQOL in patients with CHB or CHC. Age and sex-matched healthy subjects were studied as controls. Patients and methods: Prospectively, 156 consecutive patients with CHB (n=78) or CHC (n=78) and healthy subjects (n=39) underwent clinical and psychiatric evaluation. All subjects completed a survey that included Mini-International Neuropsychiatry Interview (MINI-Plus 5. 0), Hamilton Depression Rating Scale and Hospital Anxiety and Depression Scale. HRQOL was evaluated by Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). The protocol was approved by Ethical Board of UFMG. Data were analyzed with SPSS 17. 0. Hierarchical multiple linear regression analyses were used in order to quantify the simultaneous and mutually independent contribution of clinical, psychiatric and sociodemographic variables. Results: Baseline characteristics were: CHB [mean age 44. 6 ± 10. 4 yrs; 54. 6% male; 9% compensated cirrhosis and 11. 4% current Major Depression Disorder (MDD)]; CHC (mean age 46. 5 ± 8. 5 yrs; 54. 6% male; 17. 9% compensated cirrhosis and 37. 2% MDD); healthy subjects (mean age 46. 9 ± 5. 3 yrs; 54. 6% male; and 2. 6% MDD). Reduced HRQOL (in 8 domains of SF-36) was observed in patients with CHB or CHC compared with healthy subjects. No significant HRQOL difference was verified among CHB or CHC patients, excluding the domain “social aspects” that scores were more reduced in CHC patients. In CHB patients, reduced HRQOL was independently associated with cirrhosis, MDD and advanced age. In CHC patients, MDD was associated with lower scores in 7 domains of the SF-36. Furthermore, worse quality of life was found in CHC patients with systemic arterial hypertension, cirrhosis, illicit drug abuse/dependency. Conclusions: Various factors may influence the quality of life and should be monitored in follow-up of patients with chronic viral hepatitis. In the care of CHB or CHC patients, optimization of HRQOL should be considered an essential therapeutic measure. PROEX, PRPq, CAPEs, CNPq


The following people have nothing to disclose: Carolina L. Goncalves, Marina C. Loures, Luciana R. da Cunha, Claudia C. da Cunha, Fernando S. Neves, Rosangela Teixeira, Luciana D. Silva


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Influence of human T-lymphotropic virus type 1(HTLV-1) co-infection on the development of hepatocellular carcinoma in patients with hepatitis C virus infection

Mayumi Tokunaga1, 2, Hirofumi Uto1, Kohei Oda1, Seiichi Mawatari1, Masahito Tokunaga1, 2, Kouichi Haraguchi1, 3, Kotaro Kumagai1, Makoto Oketani1, Akio Ido1, Nobuhito Ohno4, Atae Utsunomiya2, Hirohito Tsubouchi5
1Digestive and Lifestyle Diseases, Kagosima University Graduate School of Medical and Dental Sciences, Kagoshima,Japan; 2Hematology, Imamura Bun-in Hospital, Kagoshima, Japan; 3Hematology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan; 4Hematology, Ikeda Hospital, Kagoshima, Japan; 5HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Aim Human T-lymphotropic virus type 1(HTLV-1) is a retrovirus that infects lymphocytes, similar to human immunodeficiency virus (HIV). HIV co-infection is known to worsen the clinical course of hepatitis C virus (HCV) infection. However, the clinical characteristics of patients with HTLV-1/HCV co-infection are not fully elucidated. The aim of this study was to investigate whether HTLV-1 co-infection influences the clinical characteristics of patients with HCV infection in HTLV-1 endemic area in Japan. Materials and Methods This retrospective study included 523 consecutive patients from January 2001 to December 2008 with chronic liver disease (CLD) due to HCV infection, in whom serum anti—HTLV-1 antibody had been examined. Among these 523 patients, 265 were diagnosed with hepatocellular carcinoma (HCC). Results The seroprevalence of anti—HTLV-1 antibodies was 15. 8% (83/523) in patients with CLD due to HCV infection. The median age of patients with HTLV-1/HCV co-infection was significantly higher than those with only HCV infection (68 vs. 66 years, P=0. 02), but serological markers such as platelet count, ALT, y-GTP, total bilirubin, and albumin were similar. The seroprevalence of anti—HTLV-1 antibodies was significantly higher in patients with HCC (21. 1% [56/265]) than those without HCC (10. 5% [27/258], P=0. 001). This difference was observed in female patients (29. 5% [28/95] vs. 8. 5% [12/142], P<0. 001), but not in male patients (16. 5% [28/170] vs. 12. 9% [15/116], P=0. 501). In addition, anti—HTLV-1 antibody positivity was independently associated with HCC in female patients with HCV infection (odds ratio [OR], 5. 02; 95% confidence interval [95% CI], 1. 76—14. 34; ト=0. 003), in addition to age (>65 years, OR, 10. 26; 95% CI, 4. 31—24. 47; P<0. 001), platelet count (<15x104/μl, OR, 2. 71; 95% CI, 1. 05—7. 00, P=0. 04), total bilirubin (>1mg/dl, OR, 3. 15; 95% CI, 1. 36-7. 28, P=0. 007), and total cholesterol (<160mg/dl; OR, 2. 91; 95% CI, 1. 34-6. 33, P=0. 007). In contrast, although age, platelet count, albumin and alcohol consumption were independently associated with HCC in male patients with HCV infection, HTLV-1 co-infection was not associated with HCC. Conclusion HTLV-1 co-infection may contribute to the development of HCC in patients with HCV infection, especially in females.


Makoto Oketani - Grant/Research Support: Bristol-Myers Squibb

Hirohito Tsubouchi - Grant/Research Support: MSD, Chugai Pharmaceutical, Kan Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi; Speaking and Teaching: MSD, Tanabe Mitsubishi

The following people have nothing to disclose: Mayumi Tokunaga, Hirofumi Uto, Kohei Oda, Seiichi Mawatari, Masahito Tokunaga, Kouichi Haraguchi, Kotaro Kumagai, Akio Ido, Nobuhito Ohno, Atae Utsunomiya


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Hepatitis C Virus Testing in Patients Undergoing Colorectal Cancer Screening at an Urban Medical Center Before and After the New CDC Recommendation

Carrie Wong, Simi K. Singh, Craig Gluckman, Albert Min
Beth Israel Medical Center, NEW YORK, NY

Hepatitis C virus (HCV) infection resulting in cirrhosis and hepatocellular carcinoma is a leading cause of liver transplantation worldwide. Nearly 3/4 of HCV patients in the U. S. are “baby boomers, ” yet many remain undiagnosed. The Centers for Disease Control and Prevention (CDC) recently recommended HCV screening in those born during 1945-1965. Our aim was to assess the new CDC recommendation's immediate impact on HCV testing among our patients undergoing colorectal cancer screening (CRCS). Methods: We reviewed the charts of all patients born in 1945-1965 who underwent CRCS as outpatients at our urban medical center between 5/2012 and 11/2012, 3 months before and after the new CDC recommendation. Results: There were 740 patients (405 women; 55%) with 319(43%) whites, 204(28%) Latinos, 160(21%) blacks and 57(8%) Asians. About 1/4 of the total (189; 26%) were screened for HCV, and 45(24%) patients tested positive for anti-HCV. Of those 189 (103 men; 55%) screened for HCV, 12(6%), 115(61%) and 62(33%) were in their 4th, 5th and 6th decades, respectively. The number of patients who underwent CRCS before (354; 48%) and after the CDC recommendation were similar. More received HCV screening (105/354; 30%) before the CDC recommendation than after with 84/386 (22%) [p=0. 058]. Among those screened for HCV, 28/105 (26. 7%) and 17/84 (20. 2%) patients tested positive for antiHCV before and after the CDC recommendation, respectively [p=0. 417]. A majority were first screened by their primary care physicians (120; 64%); 60 each before and after the CDC recommendation. Screening by sub-specialists decreased during the 3 months after the CDC recommendation. More patients received serologic tests for hepatitis B virus (HBV) (531; 72%) than for HCV (189; 26%). For our HCV patients, most were screened for HBV (42/45) and hepatitis A (39/45). Most of the HCV patients (37; 82%) had been diagnosed before coming for CRCS; 21(57%) before and 16(43%) after the CDC recommendation. Many HCV patients already had evidence of chronic liver disease on initial imaging; 6(18%) with steatosis and 15(44%) with cirrhosis before CRCS. IVDU was the most common etiology of HCV infection (26; 70%), and 4 (11%) had HIV co-infection. Most HCV patients were eligible for treatment (29; 78%), and 10 (34%) initiated interferon-based therapy. Conclusions: A minority of “baby boomers” undergoing CRCS were tested for HCV both before and after the CDC recommendation. Thus, increasing the awareness of the new CDC recommendation for HCV screening to healthcare providers and the general public will be important as better therapeutic regimens become available in the near future.


Albert Min - Consulting: Bristol Myers Squibb, Gilead, Vertex; Grant/Research Support: Bristol Myers Squibb, Gilead, Vertex; Speaking and Teaching: Bristol Myers Squibb, Gilead, Vertex, Kadmon, Merck, Salix

The following people have nothing to disclose: Carrie Wong, Simi K. Singh, Craig Gluckman


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A Prospective Study of The Association of Body Morphometry With Hepatic Steatosis and Fibrosis in HIVHCV Coinfected Patients

Chadi M. Awad, Tuyet A. Nguyen, Puneet Puri, Arun J. Sanyal, Velimir A. Lukefic, R. Todd Stravitz, Mohammad S. Siddique, lono Bouneva, Richard K. Sterling
Virginia Commonwealth University, Richmond, VA

Background: Hepatic steatosis is prevalent in those with HIVHCV and may affect the the natural history and reduce the response to anti-HCV therapy. Abnormal body morphometry (BM) is common in those with HIV. However, its association with steatosis and fibrosis in HIV-HCV has not been defined. Aim: To determine the prevalence and association between BM measures and steatosis and fibrosis in HIV-HCV patients (pts). Methods: In this prospective study, data from HIV-HCV pts seen were analyzed. At the time of biopsy, demographic, laboratory and clinical data on the presence or absence of diabetes (DM) and hypertension (HTN) were recorded. BMI, waist circumference (WC), % body fat by anthropomorphic skin fold (SF) and bioimpedience (BI) measurements were obtained by a registered dietician. Histology was assessed for steatosis (Brunt) and fibrosis (Ishak) scores blinded to clinical data. Univariate analyses were used to determine associations with the presence of steatosis (>5%) and advanced fibrosis (bridging fibrosis or cirrhosis). Multivariate logistic regression analyses were used to control for confounders including age, sex, race, and HCV genotype (GT). Results: Of 354 initial biopsies, complete BM data were available on 135 pts. Those included were similar to those with incomplete data. The mean (SD) age of the cohort was 49 (9) years, 19% were whites, and 71% were male. BM showed the mean (SD) BMI of 27 (5), WC 91. 5 (14) cm and 65% were obese (% body fat by SF: >32 for women and >25 for men). Steatosis (>5%) was seen in 17% and advanced fibrosis in 14%. Body fat assessed by SF correlated highly with BI (r= 0. 82; p<0. 0001). On univariate analysis, steatosis was associated with white race (OR 2. 78), increasing BMI (OR 1. 1) and WC (OR 1. 05). On multivariate analysis, for every % increase in body fat by SF, the risk of steatosis increases by 16% (p=0. 005), and for each cm increase in waist, the risk for having steatosis increases 5. 6% (p=0. 0039). Pts with abdominal obesity were at 6. 62 fold increased risk for steatosis compared to those without abdominal obesity defined by ATPIII criteria. On a univariate analysis, degree of fibrosis was only associated with age. Conclusions: Abnormal BM and obesity were common in our HIV-HCV cohort. Body fat assessed by SF correlated highly with BI supporting its use in clinical practice. Abnormal BM, assessed by SF, WC, and BMI were independently associated with steatosis but not associated with advanced fibrosis. Future studies on the impact of improved body morphometry and weight reduction on steatosis and its impact on the natural history of HCV in HIV coinfection are needed.


Puneet Puri - Advisory Committees or Review Panels: Health Diagnostic Laboratory Inc.; Consulting: NPS Pharmaceuticals Inc.

Arun J. Sanyal - Advisory Committees or Review Panels: Gore, Gilead, Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Bayer-Onyx, Genentech, Norgine, GalMed, Novartis, Echosens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, Gilead; Independent Contractor: UpToDate

Velimir A. Luketic - Grant/Research Support: Intercept, Merck, Idenix, Vertex, Gilead, BMS, Novartis, abbvie, Genfit, Takeda

R. Todd Stravitz - Grant/Research Support: Exalenz Biosciences, LTD

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

The following people have nothing to disclose: Chadi M. Awad, Tuyet A. Nguyen, Mohammad S. Siddique, Iliana Bouneva

Actual peak ALT values that supported aHCV diagnoses, vs closest values (CV) to time of report, and actual earliest and highest values reported.

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Acute HCV in Massachusetts: Evidence of Systematic Underreporting to CDC

Shouno Onofrey1, Jasneet Anejo2, Gillian A. Honey1, Ellen H. Nagami4, 5, Alfred DeMaria1, 4, Melinda J. Bowen6, Noelle Cocoros1, Barbara H. McGovern7, 8, Daniel R. Church1, Arthur Y. Kim2, 3
1Massachusetts Department of Public Health, Jamaica Plain, MA; 2Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA; 3Harvard Medical School, Boston, MA; 4Horvord Center for AIDS Research, Boston, MA; 5Boston University School of Public Health, Boston, MA; 6University of Massachusetts Correctional Healthcare, Worcester, MA; 7Tufts Medical School, Boston, MA; 8Abbvie Pharmaceuticals, North Chicago, IL

Background: Most acute hepatitis C virus (aHCV) infections in the U. S. occur in people who inject drugs. In 2010, 850 cases of aHCV were reported to the Centers for Disease Control and Prevention (CDC); these were used to estimate national incidence of hCv at ∼17, 000. Methods: At two hospitals and in a prison system in Massachusetts (MA), 188 persons were clinically diagnosed with aHCV from 2001-2011. aHCV was defined as seroconversion or a new diagnosis with risk factor and supporting ALT/HCV RNA. By examining reports received by the MA Dept. of Public Health (MDPH), we determined the proportion of aHCV diagnoses reported to MDPH and the proportion confirmed as aHCV cases using CDC classification guidelines. Results: Of 188 clinical cases of aHCV, 149 (79%) were reported to MDPH. Of these, MDPH reviewed 43 reports as potential aHCV cases; ultimately 1(0. 53%) met the CDC case definition and was counted in nationwide statistics. Changes in the CDC aHCV case definition in 2012 relaxed requirements for HAV and HBV testing and added HCV seroconversion; these changes would have led to confirming an additional 29 aHCV cases to the CDC, but would not have increased cases investigated by MDPH. Misclassification was often related to missing data regarding jaundice/ALT, particularly peak ALT values. Complete capture of peak ALT and seroconversions within 12 months would have confirmed an additional 31 and 9 cases, respectively. Conclusions: Clinical diagnoses of aHCV were grossly underrepresented among confirmed cases reported by MDPH to CDC, despite our enhanced surveillance system. The new CDC definition increases case ascertainment; however, incomplete clinician reporting, problematic classification requirements, and imperfect data capture remain major limitations. Our findings have important implications for national estimates of aHCV incidence.


Barbara H. McGovern - Employment: AbbVie

Arthur Y. Kim - Consulting: Abbvie, Gilead; Grant/Research Support: BristolMyers Squibb

The following people have nothing to disclose: Shauna Onofrey, Jasneet Aneja, Gillian A. Haney, Ellen H. Nagami, Alfred DeMaria, Melinda J. Bowen, Noelle Cocoros, Daniel R. Church


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Hepatic Steatosis and Insulin Resistance are associated to Vitamin D Deficiency (VDD) in Hepatitis C monoinfection and HIV/HCV coinfection

Mario P Gonzalez1, 3, Giselle B. Klautau1, Maria Cassia MendesCorrea2, Daniel F. C. Mazo3, Roberta S. Nogueira4, Flair J. Corrilho3, Mario G. Pessoa3
1Outpatients Clinic, Instituto de Infectologio Emilio Ribas, São Paulo, Brazil; 2Parasitary and Infectious Diseases Division, University of São Paulo, são Poulo, Brazil; 3Department of Gastroenterology and Hepatology, University of São Paulo, São Paulo, Brazil; 4Outpatients Clinic, Centro de Referéncia e Treinomento em DST/aids, São Poulo, Brazil

Background and Aims: Vitamin D plays a role in metabolic syndrome and has also been suggested as an immunomodulator. Lower levels are correlated with severe fibrosis in HIV/HCV coinfected and predict lower response to treatment in HCV monoinfected individuals. We performed this study with the aim to evaluate levels of 25(OH)vitamin D among a population of HCV, HIV and HIV/HCV coinfected patients and describe associated factors Methods: We collected 25(OH)vitamin D samples, demographic data, clinical information, liver biopsy results and laboratory tests including liver function and metabolic assessment of four groups of patients; 1-HCV monoinfected, 2-HIV monoinfected, 3-HIV/HCV coinfected, followed at 1 reference centers in sao Paulo City-Brazil and 4- Healthy Volunteers Control Group. Results: 422 patients were included for analysis, (129)Group 1, (118)Group 2, (53)Group 3 and (122)Group 4. Mean levels of Vitamin D were similarly insufficient in all groups including the Control Group. In an overall analysis, VDD (serum levels <20 ng/mL) was associated with HOMA index >5 (p=0, 02 OR=2, 68 95%CI: 1, 17-6, 14). Hepatic steatosis determined by liver biopsy in 160 patients of group 1 and 3 was associated with severe VDD (<10 ng/mL) (p=0, 043 Fisher Test). When analyzed by Groups, Vitamin D deficiency was associated with: 1-HOMA index > 5 in HCV patients (Graphic 1 p=0, 016 OR=5, 59 95%CI: 1, 37-22, 7), 2HOMA index > 5 in HIV/HCV coinfected patients (p=0, 028 Fisher test) Conclusion The association between Insulin Resistance (IR), Steatosis and VDD has been demonstrated in other populations, but it was not previously described in HCV and HIV/HCV coinfected patients. This finding is relevant because both IR and VDD are related to development of NAFLD and poor treatment outcomes of Interferon-based regimens. The mechanism of the association of vitamin D and NAFLD is believed to be related to oxidative stress and inflammation.


Mario G. Pessoa - Advisory Committees or Review Panels: Roche, MSD, Janssen, Johnson & Johnson, Boehringer Ingelheim, Abbott

The following people have nothing to disclose: Mario P. Gonzalez, Giselle B. Klautau, Maria Cassia Mendes-Correa, Daniel F. C. Mazo, Roberta S. Nogueira, Flair J. Carrilho


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A novel method comparing sexual networks with the HCV phylogeny in HIV-positive men who have sex with men (mSM) with acute HCV infection identifies two potential intervention targets for permucosally-transmitted HCV

Daniel Bradshaw1, Brendan Jacka1, Rachel Sacks-Davis2, Francois Lamoury1, Tanya L. Applegate1, Gregory J. Dore1, Ian Down1, Fabio Luciani3, Margaret Hellard2, Joe Sasadeusz4, Mark Danta3, Gail Mathews1
1Kirby Institute, University of New South Wales, Sydney, NSW, Australia; 2Burnet Institute, Melbourne, VIC, Australia; 3Faculty of Medicine, University of New South Wales, Sydney, NSW Australia; 4Royal Melbourne Hospital, Melbourne, VIC, Australia

Aims We aimed to identify sexual networks for sexually-transmitted HCV which might facilitate public health intervention. Methods Men with acute and recent (<12 months, AHCV) or chronic (>12 months, CHCV) HCV were recruited prospectively in Sydney and Melbourne. For MSM with AHCV 2-mode social networks showed links between men and sex venues. These were transformed into 1-mode networks showing links between men who sourced sex partners from the same venues. Sanger sequencing of HCV RNA 5'UTR-HVR1 and NS5B was performed and results compared to 76 sequences obtained for both regions from participants with AHCV from the Australian Trial in Acute Hepatitis C and CHCV from the Health in Men / Positive Health cohorts. Maximum likelihood phylogenetic trees were constructed and branch support assessed via bootstrapping (cut-off > 90%). Univariate analysis showed factors associated with clustering. Significant factors (p<0. 05) were included in a multivariate logistic regression (MLR). Significance of the Jaccard correlation (p<0. 05) between 1-mode networks and clustering was assessed via the quadratic assignment procedure. Results Table 1 shows participant characteristics. Overall 4 clusters and 7 pairs for genotype 1a (32/69, 46%) and 2 clusters and 1 pair for 3a (8/48, 17%) were found. Most clusters/pairs (26/40, 65%) comprised participants from 2 cohorts; 29/40 (73%) exclusively involved 1 city; 18/40 (45%) included a mix of sexual and IDU risk factors. MLR identified HIV coinfection (OR 16. 4 95%CI 5. 7-47. 4 p<0. 001) and sexual HCV acquisition (OR 6. 1 95%CI 2. 6-14. 2 p<0. 001) as significantly associated with clusters. Comparison between the phylogeny and 1-mode network showed clusters were significantly correlated with sourcing sex partners at the same venue (p<0. 001). One sauna in Melbourne and 3 internet sites in Sydney were key to their networks. Discussion Results imply ongoing sexual HCV transmission in HIV-positive MSM; 2 potential sites for intervention are identified.

Table 1. Characteristics for individuals recruited prospectively with (A1) AHCV and (C1) CHCV and retrospectively with (A2) AHCV and (C2) CHCV

Number of participants (%)2471225
Years of recruitment2008-20132004-20082010-20132001-2007
Median age (IQR) in years44 (34-49)34 (25-42)51(44-56)46 (43-48)
Male (%) 24(100)54 (76)22(100)5 (100)
HIV-positive (%)23 (96)24 (34)12(55)2(40)
Likely sexual acquisition (%)23 (96)16(23)6(27)1(20)
IDU ever (%)12(50)51(72)17(77)3(60)
Genotype la (%)15(63)41(58)11(50)2(40)
Genotype 3a (%)8(33)30 (42)7(32)3(60)
Number in a pair/cluster (%)15(63)18(25)6(27)1(20)


Gregory J. Dore - Board Membership: Roche, Merck, Janssen, Gilead, BristolMyers Squibb, Abbvie; Grant/Research Support: Roche, Merck, Janssen, Gilead, Bristol-Myers Squibb, Abbvie, Vertex; Speaking and Teaching: Roche, Merck, Janssen, Gilead

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

Gail Matthews - Consulting: Viiv; Grant/Research Support: Gilead Sciences; Speaking and Teaching: BMS, MSD

The following people have nothing to disclose: Daniel Bradshaw, Brendan Jacka, Rachel Sacks-Davis, Francois Lamoury, Tanya L. Applegate, Ian Down, Fabio Luciani, Margaret Hellard, Mark Danta


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Chronic Hepatitis C Treatment Failure with current NS3/4A protease inhibitors

Omar Mousa2, Chang H. Kim3, Ly-Elaine Pham4, Chukwuma I. Egwim 1, Scott A. Zela1, Victor Ankoma-Sey1
1Hepatology, Liver Associates of Texas, Houston, TX; 2Internal Medicine, State University of New York - Upstate Medical University, Syracuse, NY; 3School of Medicine, State University of New York - Upstate Medical University, Syracuse, NY; 4School of Medicine, University of Texas Health Science Center, San Antonio, TX

Background/Aim: Limited data exist regarding factors that predict failure to achieve sustained virologic response (SVR) to the direct acting agents (DAAs); Telaprevir (TVR) and Boceprevir (BVR) during chronic hepatitis C (CHC) triple therapy. Predictors of relapse (R) or Non-response (NR) to DAAs is not well established. Methods: CHC patients receiving response guided triple therapy at the Liver Associates of Texas were eligible for inclusion. They provided informed consent and futility rules were strictly applied during follow up between July 2011 and May 2013. Endpoints included the detection of significant predictive factors of non-response to triple therapy, identification of the potential causes of treatment failure (R and NR to DAAs), and causes of discontinuation. Logistic regression models for treatment response at ETR, SVR12, and SVR24 were built using the statistical software package R, version 2. 10. 1 with the following predictor variables: extended rapid virologic response, pretreatment category, genotype, race, gender, age and BMI. Significance testing for each predictor was based on the z-statistic. Results: 107 CHC patients out of 113 (Male 47. 1%, mean age 54. 5 (SD 8. 01), mean BMI 30. 2 Kg/m2 (SD 6. 51)), who reached the end of treatment week were enrolled and analyzed. 47 patients in total discontinued therapy; 44. 7% (38/85) in the TVR cohort and 32. 1% (9/28) in the BVR cohort. 3. 5% (3/85) relapsed and 10. 6% (9/85) were NR to TVR. 7. 1% (2/28) relapsed and 21. 4% (6/28) were NR to BVR. The table shows the outcomes of current DAA treatment. Based on the odds ratios, prior NR to peginterferon/ribavirin was a predictor of non-response to DAA treatment as follows: at ETR (OR: 0. 125, p: 0. 0058), SVR12 (OR: 0. 146, p: 0. 0156) and at SVR24 (OR: 0. 11, p: 0. 0094). BMI was a predictor of non-response at SVR12 only (OR: 0. 894, p: 0. 0423). Conclusion: Non-Responder (NR) to previous CHC treatment with P/R is a statistically significant predictor for treatment nonresponse with the current DAAs. This suggests that interferon responsiveness still plays a role in treatment response in the era of DAAs. BMI is a significant negative predictor of SVR12.

Table 1: Outcomes of current DAAs therapy

TreatmentNaivePrevious Non-RespondersPrevious RelapsersTreatmentNaivePrevious Non-RespondersPrevious Relapsers
Discontinuation due to: - Viral Breakthrough Non-Response to DAAs Serious adverse event - Other (e. g lost insurance)2 160987 1102 100 1 006200000
Relapse to direct acting agent111110


Chukwuma I. Egwim - Advisory Committees or Review Panels: Bristol Myers Squibb, Gilead; Speaking and Teaching: Onyx Pharmaceuticals, Gilead

Scott A. Zela - Advisory Committees or Review Panels: Gilead; Speaking and Teaching: Merck, Vertex

Victor Ankoma-Sey - Advisory Committees or Review Panels: Salix, Genentech, Merck, Vertex, BMS; Grant/Research Support: Gilead sciences, Novartis, BMS, J&J, Abbott; Speaking and Teaching: Salix, Genentech, Merck, Vertex, BMS

The following people have nothing to disclose: Omar Mousa, Chang H. Kim, LyElaine Pham


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High Prevalence of Hepatitis C Virus in Asian-Americans: Results of Office-Based Primary Care Screening

Oliver Lin1, Christine Y. Chang2,3, Joyce Y. Lee4, Ailinh Do1, Marina H.Martin5,3, Andrew B. Martin6,3, Mindie H. Nguyen1,3
1Division of Gastroenterology and Hepatology Stanford University Medical Center, Palo Alto, CA; 2Stanford University, Palo Alto, CA; 3Pacific Free Clinic, Son Jose, CA; 4School of Medicine, Stanford University, Palo Alto, CA; 5Internal Medicine, Stanford University, Palo Alto, CA; 6Center for Clinical Informatics, Stanford University, Palo Alto, CA

Purpose: According to the World Health Organization, of the estimated 170 million persons infected with HCV worldwide, only 22 million are from the Americas and Europe, compared to 94 million from Asia. HCV prevalence in the general US population is 1. 6%, but data in Asian-Americans is limited. Our goal was to examine HCV prevalence in Asian-Americans in a large ethnically diverse patient cohort seeking primary care at a free clinic in Northern California. Methods: A total of 1347 consecutive patients were seen from September 2009 to October 2012 and were studied via individual chart reviewed using a case report form. HCV infection was defined by positive HCV antibody (anti-HCV) or HCV RNA PCR. Results: Of these 1347 patients, 698 patients were screened for HCV. There were no statistically significant differences in regards to age, sex, or risk exposure profile between screened vs. unscreened patients. Of the 698 screened patients (299 non-Asians and 399 Asians), 29 (4. 1%) patients tested positive for HCV. Of these 29 HCVpositive patients, 22 of these patients were Asian, yielding a prevalence of 5. 5% for Asians and 2. 3% for non-Asians (p=0. 038). Within the Asian subgroups (216 Vietnamese, 83 Chinese, 100 other or unspecified Asian ethnicities), the highest HCV prevalence was seen in Vietnamese at 7. 9%, compared to 6. 0% in Chinese, and 0% in the Others/Unspecified group (p=0. 018). Of the HCV-positive Asians, none had a history of IVDU, tattoos, or sexual exposure. On multivariate analysis, significant independent predictors for positive HCV infection were male gender (OR=2. 53, p=0. 02) and presence of known risk factors (OR=21. 1, p<0. 001); however, there were also clear trends for older age and Asian ethnicity to be significant predictors of HCV infection (OR=1. 03, p=0. 05 and 2. 31, p=0. 066, respectively). Conclusions: In the current study, HCV prevalence in patients seeking routine primary care was 5. 5% in Asian-Americans, which was over double the prevalence for non-Asians at 2. 3%. Known risk factors were also notably absent in Asian patients with HCV infection. The high prevalence of HCV in Asian-Americans is likely reflective of the higher prevalence of HCV of their birth countries in Asia. AsianAmericans immigrants from endemic countries are at higher risk of HCV infection and should be screened for HCV regardless of their exposure risk profile.


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: Oliver Lin, Christine Y. Chang, Joyce Y. Lee, Ailinh Do, Marina H. Martin, Andrew B. Martin


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Hepatitis C Virus (HCV) Infection is Not Associated with Diabetes in the United States Population

Consfonce E. Ruhl1, Andy Menke1, Catherine C. Cowie2, James E. Everhorf2

1Social & Scientific Systems, Inc. Silver Spring, MD; 2National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD

An association of HCV with diabetes has been reported in many studies, but few have been population-based. We examined this relationship using recent population-based data from the U. S. National Health and Nutrition Examination Survey. Methods. We studied 15, 125 adult participants in the 1999201 0 surveys with data on diabetes status and serum HCV antibody (anti-HCV) and, if positive, HCV RNA. In accordance with American Diabetes Association criteria, diabetes (diagnosed and undiagnosed) was defined as a health care provider diagnosis or serum hemoglobin A1C (A1C) >6. 5% or fasting plasma glucose >126 mg/dL; pre-diabetes as A1C >5. 7%<6. 5% or fasting glucose >100-<126 mg/dL; and normal glucose as A1C <5. 7% and fasting glucose <100 mg/dL. Odds ratios for HCV infection among persons with diabetes and prediabetes compared to those with normal glucose were calculated using logistic regression and adjusted for demographics, BMI, C-reactive protein, smoking, drinking, and blood transfusion before 1992. Among participants with normal glucose, we compared mean insulin resistance, estimated using the homeostasis model assessment method (HOMA-IR), by HCV status using linear regression. Results. The overall prevalence of antiHCV+ was 1. 7% and of HCV RNA+ was 1. 1%; diabetes was found in 10. 9% and pre-diabetes in 32. 6% of participants. The prevalence of HCV markers did not differ by diabetes status (Table). After adjusting for multiple factors, HCV markers remained unassociated with diabetes status (Table). Among persons with normal glucose, HOMA-IR (mean (SE)) did not differ in persons negative (2. 1 (0. 03)) compared to positive (1. 8 (0. 16)) for anti-HCV or in those negative (2. 1 (0. 03)) compared to positive (2. 0 (0. 23)) for HCV RNA (p>0. 05 for both). HCV markers remained unassociated with multivariate-adjusted HOMA-IR (p>0. 05). Conclusion. In the U. S. population, HCV was not associated with diabetes, or with insulin resistance among persons with normal glucose.

Prevalence and multivariate-adjusted odds ratios for HCV by diabetes status

Diabetes statusPrevalence (%) (95% CI)Adjusted OR (95% CI)Prevalence (%) (95% CI)Adjusted OR (95% CI)
Normal glucose1. 6(1. 2-2. 0)1. 00. 92 (0. 68-1. 2)1. 0
Pre-diabetes1. 8(1. 4-2. 4)1. 11 (0. 70-1. 75)1. 3 (0. 96-1. 8)1. 25 (0. 77-2. 03)
Diabetes1. 6(1. 2-2. 2)0. 85 (0. 50-1. 44)1. 2 (0. 83-1. 8)0. 92 (0. 52-1. 61)


The following people have nothing to disclose: Constance E. Ruhl, Andy Menke, Catherine C. Cowie, James E. Everhart


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Anti-HEV seroprevalence rates in HIV-infected patients determined by two commercially available assays

Sven Pischke1, Carolynne Schwarze-Zander2, Birgit Bremer1, Patrick Lehmann1, Ulrich Spengler2, Anett Gisa1, Christian P Strassburg2, Michael P. Manns1, Jurgen K. Rockstroh2, Heiner Wedemeyer1
1Gastroenterology, Hannover Medical School, Hannover' Germany; 2Gastroenterology, University Hospital of Bonn, Bonn, Germany

Introduction: Hepatitis E virus (HEV) infection is a topic of growing importance in industrialized countries, as cases of chronic HEV infections have been described in transplant recipients and HIV-infected patients. Several commercial anti-HEV assays are available. However, none of them has been approved by the FDA for routine diagnostic use. We here aimed to investigate the performance of two commonly used anti-HEV assays in a German cohort of HIV-positive individuals and to determine if HEV takes chronic courses in controlled HIV infection. Methods 249 HIV-patients recruited at one German center were tested for both HEV RNA and HEV antibodies. All patients received antiretroviral therapy according to European guidelines and all but 23 individuals had CD4+ counts above 200/μl. 210 patients (84%) were born in Europe. Anti-HEV-IgG was determined by two independent commercial assays (Wantai and MP-(Diasorin) assay. Results Importantly, none of the 249 patients tested HEV RNA positive, thus excluding cases of chronic hepatitis E in patients with controlled HIV infection. AntiHEV IgG was detected more frequently in the Wantai assay (25%, n=63) than in the MP assay (<2%, n=4, p<0. 001). All four patients who tested positive by the MP-Assay and 59 of 63 (94%) patients who tested positive by the Wantai-Assay were from Europe while non-European patients tended to test less frequently positive for anti-HEV (p=0. 055). Increasing age was associated with a higher likelihood to test anti-HEV-positive in the Wantai-assay (r=0. 232, p<0. 001). There was no association between anti-HEV positive status (neither MP nor Wantai assay) and level of ALT. Conclusions There is a huge variability in seroprevalence rates of anti-HEV antibodies in HIV-infected patients determined by different assays. This gap needs to be investigated in further studies. Still, the risk to develop chronic hepatitis E is very low in individuals with well controlled HIV infection further confirming that an intact adaptive immune response is able to clear HEV infection.

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Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Jurgen K. Rockstroh - Advisory Committees or Review Panels: Abbvie, BI, BMS, Merck, Roche, Tibotec, Abbvie, Bionor, Tobira, ViiV, Gilead, Janssen; Consulting: Novartis; Grant/Research Support: Merck; Speaking and Teaching: Abbott, BI, BMS, Merck, Roche, Tibotec, Gilead, Janssen, ViiV

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

The following people have nothing to disclose: Sven Pischke, Carolynne Schwarze-Zander, Birgit Bremer, Patrick Lehmann, Ulrich Spengler, Anett Gisa, Christian P. Strassburg