Hepatitis C Newsletter
Best of the American Association for the Study of Liver Disease (AASLD) 2012Meeting
Late Breakers 1 - 1
Clinical Trials, Cohort Studies, Pilot Studies 2 – 20
Basic and Applied Science, Pre-Clinical Studies 20 - 25
HIV/HCV Coinfection 25 - 31
Complementary and alternative medicine 31 - 34
Epidemiology, Diagnostics & Miscellaneous Works 34 - 49
Liver Cancer 40 - 57
Post Transplant – New! 57 - 62
1. A 12-Week Interferon-free Treatment Regimen
with ABT-450/r, ABT-267, ABT-333 and Ribavirin Achieves SVR12 Rates (Observed
Data) of 99% in Treatment-Naïve Patients and 93% in Prior Null Responders with
HCV Genotype1 Infection
A regimen of 3 direct acting antiviral medicines plus ribavirin was well tolerated and achieved high 12-week post-treatment viral elimination rates in both new patients and prior null responders with hepatitis C virus genotype 1 infection.
2. High Rate of Sustained Virologic Response
with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir
(Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naïve
Patients Chronically Infected With HCV Genotype 1, 2, or 3
A 24-week regimen of an all oral combination of once-daily daclatasvir (DCV) plus sofosbuvir (SOF) achieved high 12-week viral elimination rates in previously untreated patients infected with hepatitis C virus genotype 1, 2, or 3.
3. An Interferon-free, Ribavirin-free 12-Week
Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of
94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus
A 12-week interferon and ribavirin free regimen of three direct-acting antivirals, daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high 4-week post-treatment viral elimination rates in treatment-naïve patients infected with hepatitis C virus genotype 1.
4. High Efficacy Of GS-7977 In Combination
With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected
Genotype 1 Patients : Interim Analysis From The SPARE Trial
A 24-week regimen of nucleotide NS5B inhibitor GS-7977 combined with low dose ribavirin was highly effective in suppressing hepatitis C virus replication in difficult to treat patients.
Dietary Cholesterol Intake is Associated with Liver Disease Progression in Hepatitis C Infection: Analysis of the HALT-C trial. L. Yu, G. Ioannou. ABSTRACT FINAL ID: 940
It is unknown whether dietary cholesterol influences disease progression in hepatitis C virus (HCV) infection. METHODS: Using data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, we analyzed whether dietary cholesterol was associated with histological and clinical progression in patients with advanced fibrosis (Ishak fibrosis score 3 or 4) and compensated cirrhosis (Ishak fibrosis score 5 or 6). Cholesterol intake was estimated at baseline, then 1.8 years later, using the Block Food Frequency Questionnaire (FFQ). Histological progression was defined by an increase in Ishak fibrosis score of 2 or more points on repeat liver biopsy in patients with advanced fibrosis. Clinical progression was defined by: death, variceal bleeding, encephalopathy, ascites, peritonitis, hepatocellular carcinoma, CTP score ≥7 or transplantation. RESULTS: Higher cholesterol intake was associated with higher intake of other macronutrients and alcohol, younger age, male sex, higher ALT and Ishak inflammation score. Using the average cholesterol intake from patients who completed both FFQ’s (N=617), higher
cholesterol intake was strongly associated with disease progression. After adjustments for age, sex, race, cirrhosis status, body mass index, interferon treatment group, lifetime alcohol, smoking, coffee intake and other macronutrients intake, each higher quartile of cholesterol intake was associated with a 50% increase in the risk of histological or clinical progression (adjusted hazard ratio [AHR] 1.49, 95% CI 1.18-1.88, P-value for trend = 0.001). Compared to
patients in the lowest quartile of cholesterol intake (31.6–151.8 mg/day), patients in the 2nd (151.9-219.9 mg/day, AHR 1.85, 95% CI 1.04-3.20), 3rd (219.9-309.6 mg /day, AHR 2.70, 95% CI 1.52-4.80) and 4th quartile (311.8-1118 mg/day, AHR 3.26, 95% CI 1.52-6.99) had progressively increased risk of histological or clinical progression. Using cholesterol intake estimated from the 2nd FFQ (N=750), the strength of the association between higher dietary
cholesterol and histological or clinical progression was weaker, but remained statistically significant (AHR 1.27, 95% CI 1.01-1.59, P-value for trend = 0.04). Using cholesterol intake estimated from the baseline FFQ (N=765), there remained an association between higher cholesterol intake and histological progression (AHR 1.31, 95% CI 1.02-1.68, P-value for trend = 0.03), but not clinical progression (AHR 1.19, 95% CI 0.92-1.52, P-value for trend = 0.2).
CONCLUSION: High dietary cholesterol intake was associated with greater risk of disease progression in HCV patients with advanced fibrosis and compensated cirrhosis.
Importance of Hepatitis C Virus in Peripheral Blood Mononuclear Cells versus Serum of Children Suffering From Chronic Hepatitis C: Pre- and Past-Treatment. M.A. El Guindi, M. Hassan, I. El-Henawy, O. ABSTRACT FINAL ID: 1132
INTRODUCTION: Hepatitis C virus (HCV) is a major cause of liver disease and one of the most important health issues worldwide specially Egypt. The prevalence of HCV in Egyptian children ranges between 2% and 10%. Relapse of HCV after anti viral therapy is a major problem, postulating presence of extrahepatic sites suitable for HCV replication, one of which is peripheral blood mononuclear cells (PBMCs). The aim of this study is to assess HCV-RNA in PBMCs versus serum of children with chronic HCV. Subjects and METHODS: The study involved 16 children, aged 4-16 years, diagnosed with chronic HCV, and attended the Pediatric Hepatology Department, National Liver Institute, Menoufiya University. All patients were subjected to thorough clinical, radiological and laboratory tests after obtaining written informed consents from parents. All patients were HCV-antibodies positive, and serum HCV-RNA positive. Patients were treated with antiviral therapy consisting of pegIFN-α2a (180ug/1.73m2 /week subcutaneously) plus ribavirin (15 mg/kg/day orally) for 48 weeks. Reverse transcription-nested PCR was done. Retrotranscription was performed using SR1 primer (for plus strand) and SF1 primer (for minus strand) HCV-RNA was monitored in serum and PBMC preparations before, mid-treatment and at the end of treatment. RESULTS: According to the response to antiviral therapy, patients were classified into responders (5 patients who achieved SVR) and non-responders (11 patients stopped treatment at 24 weeks). At the time of diagnosis
(retrospectively), HCV RNA plus strands were detected in PBMCs of all responders and in PBMCs of 10 of the non responders (90.9%). HCV RNA minus strands were detected in PBMCs of only one of the responders (20%) while they were detected in PBMCs of 9 of the non responders (81.8%) (p- value < 0.05). After 24 weeks of antiviral therapy, 5 patients were negative for HCV-RNA in serum while only 3 of them patients were negative for HCV-RNA in
PBMCs. After 48 weeks of antiviral therapy, all 5 patients were negative for HCV-RNA in serum while 2 of them (40%) still had HCV-RNA plus strand in their PBMCs. Those 2 patients received additional 24 weeks antiviral therapy till PBMCs became free of HCV-RNA.
CONCLUSION: Patients with minus strand HCV RNA in PBMCs showed a significantly lower response to IFN, suggesting that minus-strand HCV RNA in PBMCs is one of the factors predicting response to IFN therapy. PBMCs infected with HCV can serve as a virus reservoir. HCV RNA serum negative patients who had HCV RNA in their PBMCs after completion of antiviral therapy (40%) would be at great risk of HCV recurrence and treatment should be continued till PBMCs are free.
Hepatitis C virus (HCV) genotype 1 (G1) infection with low viral load (LVL) and rapid virologic response (RVR) to peginterferon and ribavirin (PEG/RBV) can be treated without a protease inhibitor (PI), irrespective of IL-28B status or patient ethnicity.
B. Pearlman, C. Ehleben. ABSTRACT FINAL ID: 151
BACKGROUND: G1 patients with LVL represent about 20% of all G1 infections. Abbreviated 24-week PEG/RBV regimens have been recommended for G-1 LVL patients that achieve RVR (nearly half). The current standard-of-care for G1 patients is PEG/RBV/PI; yet, no prospective trial has shown that a PI may be obviated in selected patients without adversely impacting SVR rates. It is also unclear if African American (AA) patients can benefit from the same treatment truncation strategy. METHODS: Therapy-naïve LVL (<600,000 IU/ml) GI patients from 2 Atlanta clinics (n=249) were treated with 4 weeks of PEG-alfa2b (1.5 mcg/kg/wk) plus RBV (1-1.2 gm/day), and if RVR was achieved, were randomized 1:1 into 24 weeks additional PEG/RBV/boceprevir (800 mg tid) [28 weeks total therapy, GROUP A] or 20 weeks additional
PEG/RBV [24 weeks total therapy, GROUP B]. Patients were stratified by IL-28B genotype (rs12979860). Primary endpoint was SVR-12. RESULTS: Of 179 patients, 49% (n=88) achieved RVR and were randomized to group A (n=41) or to group B (n=38). Baseline characteristics were not significantly different between groups including mean age, mean BMI, percentage male subjects, percentage with impaired fasting glucose, genotype subtype (1a 39 vs. 37%; 1b 61% vs. 63%), IL-28B status (CC 66 vs. 66%; non-CC 34 vs. 34%), F3/F4 fibrosis (20 vs. 18%), AA subjects (32 vs. 34%), in groups A and B, respectively. Overall SVR rates were not statistically different between Groups A and B (90 vs. 89%, respectively p=0.8). Relapse rates were 3% in Group A and 6% in Group B (p=0.52). Regardless of IL-28B genotype, SVR rates were similar between groups (C/C 96% in both groups, p=0.51; non-CC 79 vs. 77%, in groups A and B respectively, p=0.72 ) AA SVR rates were 78% in group A and 83% in group B (p=0.67). G1b patients achieved higher SVR rates relative to those of G1a in both arms (Group A G1a 81%, G1b 96%; Group B G1a 85%, G1b, 92%), yet the differences across groups were not statistically significant. Dose reductions (A 32% B29%, p=ns) and discontinuations (A 7% B 5%, p=ns) were similar between arms. CONCLUSION: This prospective, randomized trial demonstrates for G1 LVL patients who achieve a RVR with PEG/RBV, the addition of a protease inhibitor produces similar SVR rates compared to those of PEG/RBV therapy
alone, irrespective of IL28B genotype, virus subtype or African American ethnicity. Since this group comprises approximately 10% of all G1 infections, this treatment strategy may engender substantial cost savings. The study is ongoing, and results should be duplicated in larger, multicenter trials before this strategy is adopted.
Hepatitis B and C are associated with Non-Hodgkin Lymphoma: cross-sectional study of the National Inpatient Sample database. M. Moehlen, A. Abbas, L.A. Balart. ABSTRACT FINAL ID: 907
BACKGROUND: Independent associations of hepatitis B (HBV) and C (HCV) to non-Hodgkin lymphoma (NHL) have been previously reported, although proven links have not yet been established. AIM: Assess the associations of HBV and HCV with NHL in a large nationwide cohort within the United States. METHODS: We performed a cross-sectional study using the National Inpatient Sample database for the years 2005-2009. All discharges of adults that contained ICD-9 codes for HBV and HCV were included as the hepatitis group (exposed).
An equal number of non-hepatitis diagnosed patients randomly sampled from the database served as the comparison group (non-exposed). NHL was identified in each group using ICD-9 codes and the rates were compared using standard statistical methods. A multivariate logistic regression analysis was used to assess the independent effect of hepatitis on the outcome of NHL. RESULTS:A total of 1,055,912 patients’ discharges were included in the analysis. Discharges that contained HCV ICD-9 codes were 479,661 (45%) while those with HBV were 48,295 (5%), the rest 50% represents the comparison group. Median age at admission was 53 years, male percentage was 51%, and Caucasians were 51% of the total included population.
The univariate analysis found HBV to have the highest rate of NHL, 2.1% (1,019 cases) compared to 0.82% (3,966 cases) and 0.65% (3,470 cases) for HCV and the comparison group, respectively (p<0.001). In multivariate analysis, hepatitis status was an independent risk factor for NHL with HBV having the largest effect size (OR=3.32, p<0.001) (Table). CONCLUSIONS: This is the largest cross-sectional study within the United States confirming the associations of HBV and HCV with NHL. Our results are in agreement with previous reports linking HBV and HCV with NHL. There is a limited understanding of the pathophysiology of HBV and HCV infection and the activation and transformation of B-cell lymphocytes into lymphomas. Our study highlights the need to further study these associations and implement
measures to prevent and treat HBV and HCV infection.
Factors influencing the quality of life on patients with chronic hepatitis C, evaluated with generic questionnaire SF-36. R. Teixeira, L.D. Silva, C.C. da Cunha, N.S. Monteiro, et al. ABSTRACT FINAL ID: 986
Quality of life is a complex issue that involves physical, mental, psychological and emotional wellbeing, as well as social relationships, like family and friends. Several studies have demonstrated a decrease in the quality of life on chronic hepatitis C patients with no significant liver disease. AIM: To evaluate factors associated with the decrease in quality of life on patients with chronic hepatitis C (HCV). METHODS: 125 consecutive patients with HCV were enrolled in the study. All patients completed several surveys including MINI-Plus 5.0, Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, CAGE. The quality of life was evaluated by generic questionnaire Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), with 8 domains: functional capacity, physical aspects, emotional aspects, social aspects, mental health, pain, vitality and general health condition. RESULTS: Demographic and clinical characteristics were: mean age 54.0 ± 8.9 yrs; 57.6% female; 16.8% compensated cirrhosis; 28.8% current depression and 7% and 21%, current and past alcohol dependence, respectively; 33.7% hypertensive and 19% diabetics. MDD was associated with low SF-36 scores in all domains (p<0.01). There was no association between reduction of the SF-36 score and alcoholism. The score of functional capacity domain was reduced in HCV-patients with hypertension (p=0.003) or diabetes mellitus (p <0.001) when compared to HCV-patients without these comorbidities. CONCLUSION: Several factors, in addition to the disease limited
to the liver, affect the quality of life on HCV patients. The clinical evaluation becomes relevant in the follow-up of those individuals, mainly as to the emotional, social and mental health aspects, that must be carefully investigated.
Impact of SVR on all-cause and liver-related mortality in a cohort of Veterans with chronic hepatitis C. E. Dieperink, P. Thuras, S. Colton, A. et al. ABSTRACT FINAL ID: 1010
PURPOSE: Determine whether SVR and other factors reduce all-cause and liver-related mortality in Veterans with hepatitis C. METHODS: Retrospective chart review of all patients who initiated antiviral treatment for chronic hepatitis C between 1/1/1997 and 12/31/2009 at a single VAMC. We obtained antiviral treatment type, SVR, death, reason for death, liver biopsy, problem-list co-morbidities, and whether patient was seen by the mental health practitioner in the HCV clinic using an integtrated care case management approach. Chi-Square and logistic regression were used to determine factors associated with mortality. RESULTS: Of the 541 patients, 99% (533/541) were male. Mean age at initiation of first antiviral treatment was 51.5. Liver biopsies were performed on 80% (435/541) of patients pre-treatment. An additional 34 patients had a clinical diagnosis of cirrhosis before treatment. Median follow-up was 7.5 years. As of May 15, 2012 40.5% (219/541) obtained an SVR and 19.4% (105/541) had died. Race, genotype, having cirrhosis before the first antiviral treatment, and the number of antiviral treatments had no impact on all-cause mortality. Having one of the following on the problem list had no impact on all cause mortality: stroke, heart disease, any substance use disorder, alcohol use disorder, depression, PTSD, psychosis or bipolar disorder or diabetes. Liver-related deaths were more likely for genotype 1 than genotype 2 or 3, and in cirrhotics (23.1%) vs non-cirrhotics (10.1%). Patients with SVR had significantly reduced liver-related mortality compare with non-SVR patients [2.7% vs. 18.9%, X2 (1, N=541) =31.5, p<.0001] but there was no difference in non-liver related death (5.9% vs. 7.5%). Patients seen by integrated care mental health staff were less likely to die from any cause (15% vs 23% (p=.01)) and less likely to die from liver disease
(9.4% vs 15.1 (p=.03)). In a step-wise logistic regression SVR conferred an almost 8-fold reduction in liver-related mortality (OR=.13, .056-.314), and this effect was present both in noncirrhotics (OR= .10, .03-.27) and to a lesser extent in cirrhotics (OR=.34, .07-1.6).
CONCLUSIONS: SVR significantly reduces liver-related mortality in both patients with and without cirrhosis at baseline. In addition, seeing an integrated mental health practitioner reduced all-cause and liver-related mortality. The combination of effective therapies to increase SVR rates and a strategy of integrated care protocols for patient management are important factors for reducing mortality from HCV.
Sustained Responders have Lower Rates of Liver-Related Events and a Better Quality of Life and Productivity Compared with Non-Responders/Relapsers after Antiviral Treatment of Chronic Hepatitis C. S. Mauss, J.Petersen, T. Witthoeft, et al. ABSTRACT FINAL ID: 800
BACKGROUND: Limited data exist regarding liver-related morbidity and health-related quality of life after treatment of chronic HCV infection with interferon (IFN)-based therapies in the real-life setting. We therefore conducted a non-interventional follow-up survey in German gastroenterological practices to compare long-term clinical outcome in patients who achieved sustained virologic response (SVR) or non-SVR after IFN-based HCV treatment. METHODS: Patients with chronic hepatitis C who achieved SVR / Non-SVR after IFN-based treatment ≥3 years ago and who are still under routine medical observation were enrolled by 45 gastro-enterological centers in Germany. Significant clinical events related to progression of liver disease (ascites, variceal bleeding, hepatic malignancy and liver transplantation) were recorded. Health-related quality of life (HRQOL) was assessed by the SF-36 questionnaire. RESULTS: From May 2009 until October 2010 N=1355 patients (male 58.0%, mean age 49.2 ±11.48 yrs) infected with G1 (62.4%), G2 (8.1%), G3 (26.3%) and G4/other (3.2%) have been enrolled. Median follow up was 4 yrs (range 3 to 8 yrs). 42 and 1313 pts were treated with non-pegylated / pegylated IFN in combination with ribavirin. In total 759/1355 (56%) achieved SVR after first therapy. Only 3 SVR patients (0.4%) developed a liver-related clinical event in contrast to 31 (6.2%) non-SVR patients. Of the 34 pts patients who had significant liver-related clinical events, 24 (including the 3 pts with SVR) had baseline cirrhosis. Non-SVR patients had significantly lower scores on the eight SF-36 domains (each P<0.0001) indicating lower HRQOL. In addition, non-SVR patients were more likely to have a lower productivity as assessed by a lower frequency of employment (41% vs 56%, P<0.0001), a lower number of working hours/week (27 vs 32, P=0.0031) and a higher number of outpatient (9.4 vs 5.3, P<0.0001) as well as inpatient visits (0.9 vs 0.1, P=0.0013) after HCV treatment. Regarding HRQOL and productivity, similar and significant differences were obtained following stratification by gender, age (≤50 years/>50 years), type of non-SVR (non-response/relapse) and number of antiviral treatments (1/>1).
CONCLUSIONS: SVR has a profound impact on liver-related morbidity suggesting a clinical and not only virological cure of chronic hepatitis C. In addition, SVR is associated with a better quality of life and productivity. Altogether our results demonstrate the beneficial effect of successful HCV treatment in a large real-world population.
Decreased health-related quality of life (HRQoL) in chronic hepatitis C (CHC): association with major depressive disorder (MDD), anxiety disorders, clinical comorbidity and sociodemographic factors. R. Teixeira, L.D. Silva, L.R. da Cunha, R.F. Araújo, C.C. et al. ABSTRACT FINAL ID: 980
BACKGROUND: In addition to the known morbidity and mortality, many CHC patients report reduced HRQoL as compared with healthy controls, regardless of the severity of liver disease. Mood, illness severity and health behaviour affect HRQoL in several medical disorders. In the case of HCV infection, the interrelationships among these biopsychosocial factors are not fully understood. Aims: (1)To characterize the variability of HRQoL in CHC patients and, (2)To evaluate factors that may influence HRQoL. METHODS: 125 HCV RNA-positive outpatients
were enrolled during their visit to the Viral Hepatitis Ambulatory. All patients completed several surveys including Mini-International Neuropsychiatry Interview (MINI-Plus 5.0), Hamilton Depression Rating Scale (HDRS), Hospital Anxietyand Depression Scale (HADS), Cut down, Annoyed, Guilt, and Eye-opener questionnaire (CAGE). HRQoL was evaluated by Liver Disease Quality of Life Questionnaire (LDQOL1.0), consisting of the SF-36 generic measure of HRQoL and 12 disease-specific dimensions for patients with liver disease. The protocol was approved by Ethical Board of UFMG. Data were analyzed by SPSS 17.0. A 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 of CHC patients: mean age 54.0 ± 8.9 yrs; 57.6% female; 16.8% compensated cirrhosis, 28.8% current depression and 23.2% anxiety disorders. MDD was associated with lower LDQOL scores in 10 domains, excluding sexual function(p=0.15) and sexual problems (p=0.43), independently of liver stage disease. Anxiety disorders were associated with reduction in 3 LDQOL domains: health distress(p=0.003), stigma of liver disease(p=0.007) and sexual problems (p=0.04). Worse quality of life was found in patients with current or previous alcohol abuse or dependency for the domain loneliness(p=0.009). Cirrhosis, diabetes and blood
hypertension were associated with lower LDQOL scores in 3 domains: sexual function(p=0.02), sexual problems(p=0.01) and memory(p=0.006), respectively. Higher levels of education were associated with lower LDQOL scores in 3 dimensions: health distress(p=0.02), hopelessness (p=0.02) and stigma of liver disease(p=0.04). CONCLUSIONS: These results emphasize the importance of assessing psychiatric comorbidities, especially depression and anxiety disorders and, lifestyle behaviours in HCV clinical care. There is a clear need to adopt a biopsychosocial
model of care when looking at strategies to improve HRQoL among patients living with hepatitis C.
The Impact of Lifetime Drug Use on Hepatitis C Treatment Outcomes in Privately Insured Members of an Integrated Health Care Plan. M. Pauly, R. Cunanan, G.L. Witt, et al. ABSTRACT FINAL ID: 955
PURPOSE: Despite the high prevalence of drug abuse among patients with hepatitis C virus infection (HCV), data on the relation of drug abuse to HCV treatment outcomes in insured household populations is lacking. METHODS: We previously reported the impact of alcohol in 421 treatment naïve HCV patients in an integrated healthcare plan, treated with pegylated interferon α and ribavirin between Jan 2002 and Jun 2008 (Russell et al Hepatology in press). We examined the relation of lifetime drug use to treatment outcome. For drugs used at least 5
times, a detailed lifetime frequency history was obtained in 259 (61.5%) eligible patients. Drugs assessed were marijuana; the non-medical use of stimulants, sedatives, and opioids; hallucinogens; and inhalants. Use was examined for HCV-relevant periods: prior to diagnosis; from diagnosis to treatment initiation, during the 6 mos before treatment, during treatment, and from the end of treatment to determination of sustained viral response (SVR). A drug summary measure, lifetime drug years, was calculated. Data on host and viral risk factors known to influence HCV treatment outcome were extracted from medical records or patient interviews.
FINDINGS: The prevalence of drug use was high. 3 or more drugs were used by 57.9% of patients and 61.2% had injected drugs. Most had stopped using by the time HCV was diagnosed, and patients reduced their drug intakes still further in the months prior to and during treatment (Table 1). SVR was not lower in patients using any of these drugs, using 3 or more drugs, or not abstaining 6 mos prior to HCV treatment. Nor was higher lifetime frequency of drug use
associated with lower SVR rates. A presumed clinically irrelevant, but statistically significant positive relation was observed between stimulant use and SVR, after controlling for known host and viral factors. Drug years was positively related to SVR. CONCLUSION: Drug use prior to HCV treatment did not have a negative impact on treatment outcomes in our population. A history of drug use should not be considered a deterrent to HCV treatment in members of an integrated health care plan who are motivated to seek treatment and closely monitored.
% patients using drugs in critical time periods (N=259). Prior to HCV Diag <6 mos before
Treatment During HCV treatment Marijuana 83.8 16.8 8.5 Stimulant 71.9 3.1 0.4 Opiate 38.5 1.9 1.2 Sedative 40.4 2.7 0.4 Hallucinogen 51.5 0.4 0.8 Inhalant 16.5 0.4 0.8
Factors Influencing Likelihood of Compliance in Chronic Hepatitis C with Patients Receiving Pegylated Interferon Plus Ribavirin. L. Rover, C. Escheik, L. Gerber, M. et al. ABSTRACT FINAL ID: 75
BACKGROUND: Maximizing subjects’ ability to adhere to treatment requires an understanding of relevant biological and behavioral factors. Outcomes may be aided by early identification and proper treatment. AIM: To learn if psychobehavorial measures correlate with compliance in subjects with chronic hepatitis C (HCV) treated with Pegylated Interferon and Ribavirin (PIR). METHODS: 63 subjects with HCV participated in a prospective clinical trial of PIR. History and physical examination provided sociodemographic information. Compliance scores were based on attendance and adherence to doctor’s orders. Patients with a score greater than 83% were considered compliant. Standardized patient reported outcomes were done at baseline: State Trait Anger Expression Inventory-2 scales (STAXI-2) included, Feeling Like Expressing Anger Verbally (S-Ang/V), Feeling Like Expressing Anger Physically (SAng/P), Angry Reaction (T-Ang/R), Trait Anger (T-Ang), Anger Expression-Out (AX-O), and other anger measures;
Short Form-36; Chronic Liver Disease Questionnaire–HCV (CLDQ-HCV) that measures Activity/Energy (AEM), Emotion (EMM), Worry (WOM), Systemic (SYM), and CLDQ-HCV total score. Data were analyzed using Fisher exact and Wilcoxon Mann-Whitney U tests and Spearman rank order sum. Statistical analyses were performed using SAS (v 9.3). RESULTS: Eighty-four percent completed all patient reports. Data were analyzed by comparing two groups:
45 (71%) individuals who complied to treatment (Comp) and 18 (29%) who did not (NonComp). The Comp group had a mean age of 47.4±7.4 years (62% female) with 33 (73%) married and 34(76%) employed; Non Comp, 46.6±9.4 years (67% female) with 14 (78%) married and 14 (78%) employed. Of the entire cohort, 50 individuals had genotype 1 (81% Comp; 68% NonComp). Group differences were not statistically significant. The likelihood of compliance was lower in subjects who had more self-reported symptoms of S-Ang/V (p=<.01). Subjects on anti-depressants at the start of the study reported more T-Ang/R (p=.01), T-Ang (p=.03) AX-O (p=.02), EMM (p=.04), WOM (p=.05), and SYM (p=.06); and total CLDQ-HCV symptoms (p=.03). CONCLUSIONS: HCV patients treated with PIR were less likely to be compliant if they reported more anger and worry at baseline. Subjects receiving anti-depressant medication at baseline reported significantly more symptoms on the STAXI-2 and quality of life impairment reported by CLDQ-HCV. It is beneficial to assess level of anger and worry before PIR treatment and to use psychobehavioral measures as a tool for monitoring patients during treatment and addressing their needs for interventions.
Randomized Controlled trial of Motivational Enhancement Therapy to Reduce Alcohol in Patients with Chronic Hepatitis C. E. Dieperink, P. Thuras, K. McMaken, C. et al. ABSTRACT FINAL ID: 794
PURPOSE: Randomized single blind study to determine whether Motivational Enhancement Therapy (MET) reduces alcohol use in HCV patients who are currently drinking alcohol compared to an educational control condition (EDU). METHODS: Eligible patients were recruited from the Minneapolis and Portland VA’s and were randomized to either MET or EDU. MET is a 4 session manualized treatment for patients with alcohol use problems using motivational interviewing, a directive approach designed to resolve ambivalence. The education control condition consisted of 4 sessions including: sleep hygiene, nutrition and diet, stress management and fitness and exercise. Alcohol use was measured with the time-line follow back (TLFB) at baseline, 3 months, and 6 months. Inclusion criteria were: HCV+ viral load, drinking 7 or more drinks for each of the preceding 2 weeks or having a heavy drinking day (4 or more
drinks in one day) per week for 2 weeks and having a DSM-IV alcohol use disorder. Exclusion criteria were: cocaine, methamphetamine or opioid dependence within the past 6 months, CNS trauma, significant cognitive impairment, dementia, encephalopathy, or acute psychiatric instability. A mixed-effects model was used to determine whether MET reduced alcohol use compared to the control condition. All patients signed written informed consent. RESULTS: A total of 135 subjects were randomized. Most of the subjects were male 95.6% (129/135), and white 68.1% (92/135). Mean drinking days in the past month at baseline for the MET group was 20.0 and for EDU was 20.3. At three months the MET group reported significantly fewer drinking days (9.3) compared with the education group (12.9) this difference was maintained at 6 months (8.4 vs. 12.9; F(2,242.5)=3.2, p=.042). The effect size for the difference in drinking days at 3 months Cohen’s d=.35 and at 6 months d=.40. CONCLUSIONS: MET should be considered a first-line treatment for HCV patients with alcohol use disorders who continue to drink. As MET is a brief alcohol treatment it may be ideally suited for integrated care clinics where mental health practitioners are collocated and where resources are limited.
The impact of virologic resistance and adherence on treatment failure in a cohort of hepatitis C virus (HCV) infected patients treated with telaprevir (TVR) and boceprevir (BOC). C. Velazquez, W.M. Rosenberg, C. Velazquez, S. et al. ABSTRACT FINAL ID: 1089
INTRODUCTION: Phase 3 studies show that up to 73% of patients failing treatment with TVR or BOC develop drug-resistance mutations (DRM). In this study we report the incidence and nature of treatment failure in a prospective cohort of 53 patients with chronic HCV infection treated with either TVR or BOC combined with pegylated interferon-alfa and ribavirin (PEG/R).
METHODS: All patients had baseline HCV RNA levels >10,000 IU/ml and evidence of at least bridging fibrosis. All patients treated with BOC had previously failed PEG/R treatment. Patients treated with TVR were either treatment naïve or experienced. HCV viral load was determined using a validated in-house assay. Virologic failure (VF) was defined as HCV RNA >1000 IU/ml at week 4 or 12 for patients treated with TVR or HCV RNA >100IU/ml at week 12 for those
treated with BOC respectively, or an increase of >1log10 viral load from nadir. Genotypic resistance was performed using standard population Sanger sequencing. Nested RT-PCR was used to amplify viral RNA and the first 181 amino acids of the NS3 protease were sequenced.
RESULTS: Forty two of 53 patients (79%) were treated with TVR and 11 (21%) with BOC. A total of 13 patients (25%) had VF (12 TVR, 1 BOC) of which DRMs were detected in 10 (77%). All patients who developed VF with DRMs had HCV genotype 1a and were treated with TVR. Mutations evolved at NS3 positions 155 and 36; Arg to Lys at 155 and/or Val to Met or Leu or Val/Met at 36, none of which were detected at baseline. Nine patients were treatment experienced (4null responders, 3 relapsers, 2 breakthrough) and 1 was naïve. DRMs were first detected during or after TVR triple therapy (4 at week 4, 2 at week 8, 2 at week 12 and 2 at week 24). Three patients with VF did not have identifiable DRMs by population sequencing (2 TVR, 1 BOC). In the TVR treated patients without detectable mutations VF occurred during PEG/R therapy and was detected at week 24. Both had subtype 1b and severe fibrosis (1 a previous
null responder and 1 treatment naïve).The BOC treated patient had subtype 1a HCV with moderate fibrosis and was a previous relapser. When questioned, all 3 patients reported failure to ingest a fatty meal with their medication or poor adherence to TVR or BOC. CONCLUSION:
In this cohort DRMs were identified by population sequencing in 77% of treatment failures, comparable to that seen in Phase 3 trials; all infected with HCV genotype 1a and most were treatment experienced. No novel DRMs were identified. All the patients failing treatment without DRMs reported either inability to tolerate a fatty meal or poor adherence to medication. This observation requires further investigation.
Consequences of Current Hepatitis C Direct Anti-Viral Agents (Telaprevir and Boceprevir) on the Health-Related Quality of Life. O. Mousa, L. Pham, C.I. Egwim, et al. ABSTRACT FINAL ID: 982
PURPOSE: Our aim is to evaluate the effect of the new HCV Direct Acting Agents (DAA): Telaprevir (TVR) and Boceprevir (BVR), on health-related quality of life of hepatitis C patients in a community practice. METHODS: :We administered the short form 36 (SF-36) Health-related Quality of Life Questionnaire to HCV patients undergoing treatment with TVR or BVR, as part of the pegylated interferon and ribavirin based triple therapy, at the Liver Associates of Texas Hepatology Clinics. 87 patients completed at least the baseline survey during scheduled clinic visits between 7/1/2011 and 5/31/2012 and were eligible for this interim statistical analysis. Patients attended an HCV education class and signed an informed consent before enrollment. The endpoint is to study the effect of HCV DAAs on the physical and mental health of HCV patients. SPSS v19 and Minitab v16 were used for statistical analysis. RESULTS: Data analysis was performed on 87 patients (68 in TVR group vs 19 in BVR group). 31 patients completed surveys at both baseline and week 12 (25 on TVR: 6 on BVR). Mean Age is 54 years (SD=8.4), mean BMI is 30.5 kg/m2 (SD=6.7), Males 49.4%. Analysis showed a drop in the mean scores of the eight SF-36 domains in both treatment groups at Week 12 compared to Baseline, with a relative improvement in all the SF-36 domains in the TVR group at week 24 except the Body Pain (BP). The Wilcoxon Signed Rank test was used for paired data analysis of
patients completing both baseline and week 12 surveys. Analysis of the TVR group (n=25) showed a statistically significant worsening in the health related quality of: Physical Functioning, Role Physical, Role Emotional, Social Functioning and Vitality, while analysis of the BVR group (n=6) showed a statistically significant worsening of one health domain, the Social Function (94.1% CI: 50-100 baseline, 12.5-43.8 week 12). The Mann Whitney U test was
used to compare both treatment groups at baseline and showed no significant differences in the health domains. At week 12, a statistically significant deterioration in the Social Functioning (p = 0.0273) was more evident in the BVR treatment group. CONCLUSION: The new DAAs affect health related quality of life in various ways. TVR affects both the Physical and Mental Components, whereas BVR predominately affects the Mental component and the Social
Function. These findings may be clinically relevant in the treatment of HCV patients in the era of DAAs.
VX-222, Telaprevir and Ribavirin in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C: Results of the ZENITH Study Interferon-Free Regimen. I.M. Jacobson, M.S. Sulkowski, E.J. Gane, et al. ABSTRACT FINAL ID: 231
BACKGROUND AND AIMS: ZENITH assessed the safety, tolerability and antiviral activity of VX-222 (nonnucleoside polymerase inhibitor) with telaprevir (TVR)(protease inhibitor) alone (DUAL), with ribavirin (RBV)(TRIPLE) or with peginterferon alfa-2a (Peg-IFN)/RBV (QUAD), in chronic HCV genotype 1 treatment-naïve patients. Here we present TRIPLE interim results.
METHODS: Genotype 1b (n=23, Arm E) and 1a patients (n=23, Arm F) received VX-222 400mg BID, TVR 1125mg BID, and RBV 1000-1200mg/day for 12 weeks (wks). Patients with undetectable HCV RNA at Wk 2 and 8 were eligible to stop all treatments at Wk 12; those with detectable HCV RNA at Wk 2 and/or 8 received 24 additional wks Peg-IFN/RBV. On-treatment results presented for all through Wk 12 and SVR12 for those eligible to stop treatment at 12
wks. SVR for all will be presented. RESULTS: HCV RNA was <LLOQ in 91% of Arm E/F patients at Wk 4 with 91% Arm E and 57% Arm F <LOD. 83% of E/F patients had HCV RNA <LOD at Wk 12. 3 TRIPLE patients experienced viral breakthrough (vBT); all IL28B non-
CC. 5 and 6 patients in Arms E and F, respectively, were eligible to stop treatment at Wk 12; of these, 5/5 and 4/6 achieved SVR12. Patients had NS3 and NS5B resistant variants at vBT or relapse. 2 patients (4%) withdrew due to adverse events (AE). During the TVR/VX-222 phase, most AEs were mild/moderate with diarrhea (50%), rash (37%, all mild), nausea (30%), pruritis (30%) and fatigue (24%) most common. The incidence/severity of rash and anemia were both lower than QUAD (400mg)(rash 60% with 10% moderate, 7% severe; anemia 37%).
CONCLUSIONS: In a pilot study that included an all oral, interferon-free regimen of TVR/ /VX-222/RBV, the majority of patients had undetectable HCV RNA at Wks 4 and 12, with a higher rate of HCV RNA <LOD at Wk 4 in genotype 1b. Among patients eligible to stop at Wk 12, high SVR12 rates were observed in this small pilot study, and the regimen was well-tolerated.
Twelve- or 16-Week Treatment With Daclatasvir Combined With Peginterferon Alfa and Ribavirin for Hepatitis C Virus Genotype 2 or 3 Infection: Command GT2/3 Study.
G.J. Dore, E. Lawitz, H.A. Tatum, et al. ABSTRACT FINAL ID: 762
BACKGROUND: The current recommended treatment for chronic HCV genotype (GT) 2 or 3 infection is 24 weeks (wk) of peginterferon alfa + ribavirin (peg-alfa/RBV). Combining direct-acting antivirals with peg-alfa/RBV can enhance virologic responses, potentially allowing shorter treatment durations. Daclatasvir (DCV; BMS-790052) is a first-in-class NS5A replication complex inhibitor with broad coverage in vitro against HCV GT 1-4. Study AI444-031 evaluates short-term treatment (12 or 16 wk) with DCV 60mg QD combined with peg-alfa 2a (180mcg weekly)/RBV (400mg BID) in patients with chronic HCV GT2 or 3. METHODS: Adult treatment-naïve patients with chronic HCV GT2 or 3 were randomly assigned to receive DCV + pegalfa/RBV for 12 wk, DCV + peg-alfa/RBV for 16 wk, or placebo (PBO) + peg-alfa/RBV for 24 wk. The primary efficacy endpoint is sustained virologic response 24 wk posttreatment (SVR24); we present on-treatment results through wk 16. HCV RNA assay LLOD was <10 IU/mL. RESULTS: 71 patients with GT2 and 80 with GT3 were treated. DCV 12 wk (N=50), DCV 16 wk (N=50) and PBO (N=51) arms were generally well balanced at baseline for viral and host factors that have been correlated with treatment response. More patients with GT3 vs 2 were cirrhotic (range 14.8%-26.9% vs 0%-4.2% across treatment arms); 38.5%-44.4% of patients with GT3 and 25.0%-41.7% of patients with GT2 had IL28B (rs12979860) CC genotype. Virologic response rates at wks 4 (RVR) and 12 (cEVR) were higher in both DCV arms vs PBO for GT2 and 3 cohorts (Table). Responses in DCV arms were similar for GT2 vs 3 despite a higher proportion of GT3 patients having underlying cirrhosis. All GT2 patients with IL28B genotype CC (n=23) achieved cEVR; however in GT2 patients with non-CC, cEVR rates were higher in the DCV 12 wk (12/13; 92.3%) and 16 wk (12/15; 80.0%) groups vs PBO (12/18; 66.7%). IL28B genotype had no consistent effect on cEVR rates in patients with GT3. There were 2 viral breakthroughs (DCV 16 wk, PBO). The most frequently reported treatment-related adverse events (AEs) were those typically associated with peg-alfa/RBV use, including fatigue, cytopenias, and depression. CONCLUSION: Treatment with peg-alfa/RBV/DCV enhances early viral suppression compared with peg-alfa/RBV, supporting a potential role for DCV in the treatment of chronic HCV GT2 or GT3 infection.
Peginterferon Lambda-1a (Lambda) is Associated With Less Autoimmune Thyroid Disease and Serious Autoimmune Disease Than Peginterferon Alfa-2a (Alfa) When Used in Combination With Ribavirin (RBV) for the Treatment of Chronic Hepatitis C Virus Infection. P. Fredlund, J.L.Hillson, T.E. Gray, et al. ABSTRACT FINAL ID: 781
BACKGROUND: Treatment with peginterferon alfa is associated with increased risk of autoimmune disease. Lambda exerts antiviral effects through a unique receptor with limited distribution outside the liver. In a phase 2b study of treatment-naïve patients, Lambda in combination with ribavirin (RBV) demonstrated robust virologic responses with reduced cytopenias, arthralgias, myalgias, and flu-like symptoms compared to Alfa/RBV. Here we
report the relative rates of thyroid dysfunction and serious autoimmune disease. METHODS: 525 treatment-naïve noncirrhotic patients received daily oral RBV and weekly Lambda (120, 180 or 240μg) or Alfa (180μg) for up to 24 (HCV genotype [GT] 2, 3) or 48 (HCV GT1, 4) weeks. Exploratory retrospective analysis was performed of adverse events (AE) included in the MedDRA version 14.0 SMQ Thyroid Dysfunction, serious AE consistent with autoimmune disease, and frequency of clinically significant abnormalities of thyroid stimulating hormone (TSH). Patients with TSH ≥10 mIU/L, ≤0.01 mIU/L, or both were reviewed in a blinded manner by an expert endocrinologist and classified as follows: (a) inadequate or excessive thyroid replacement in patients with pre-existing thyroid disease, (b) exacerbation of pre-existing autoimmune thyroid disease, (c) new primary hypothyroidism, (d) painless thyroiditis, (e) Graves’ disease, or (f) not determined. RESULTS: The odds of a reported AE of thyroid dysfunction was 5.2 times greater on Alfa vs Lambda. Similarly, the odds of a reported significant elevation or reduction in TSH was 5.1 times greater on Alfa. Median time to abnormal TSH was 20.14 (4.0-44.1) weeks. Blinded review found most TSH elevations reflected new-onset hypothyroidism requiring treatment, while most low TSH reflected probable painless thyroiditis and resolved without sequelae. Review of serious AEs consistent with autoimmunity revealed 4 events (1 panniculitis, 2 sarcoidosis, 1 pseudotumor cerebri) among 133 (3.0%) Alfa recipients, and 1 event (uveitis) among 392 (0.2%) Lambda recipients.
Peginterferon Lambda-1a (Lambda) is less likely to induce clinically significant neuro-psychiatric symptoms during the treatment of chronic hepatitis C virus (HCV) infection, compared to peginterferon alfa-2a (Alfa) A.J. Muir|S. Srinivasan, D. Dimitrova, J.et al. ABSTRACT FINAL ID: 793
BACKGROUND: Alfa interferons are associated with significant neurologic and psychiatric adverse events (AEs), often limiting treatment options for patients with chronic HCV infection. Lambda is a novel type III interferon that exerts its antiviral effects through a unique receptor with limited distribution outside the liver. Here we describe neuropsychiatric effects of Lambda and Alfa, using Becks Depression Inventory (BDI II) scores and reported AEs from the phase 2 EMERGE study. METHODS: Treatment–naïve, noncirrhotic patients (N=525) received daily ribavirin and weekly Lambda (120, 180 or 240μg) or Alfa (180μg) for up to 24 weeks (GT2/3) or 48 weeks (GT1/4). AEs included in the MedDRA version 14.0 SMQ Nervous System Disorder or Psychiatric Disorder, and BDI II scores (0-19, minimal/mild depression; 20-28, moderate; 29-63, severe) were examined for differences in frequency/changes from baseline for Lambda (pooled data) and Alfa. RESULTS: All comparisons are reported for Alfa vs Lambda recipients, respectively. AEs characterized as nervous system disorders were reported for 51.9% (69/133) and 39.3% (154/392). Headache (39.8% vs 26.3%) and dizziness (10.5% vs 7.9%) were reported most frequently. AEs characterized as psychiatric disorders were observed in 46.6% (62/133) vs 40.6% (159/392). Depression was reported in 11.3% vs 12%; irritability in 12.8% vs 16.6%; and affect lability in 5.3% vs 0.8%. One instance of suicidal ideation was reported in the Lambda 120 μg group. 3 patients discontinued due to psychiatric AEs: 2/133 (1.5%) in the Alfa group and 1/392 (0.25%) in the Lambda group. A greater mean increase (worsening) in BDI II score from baseline was observed at Week 48 among GT1/4 Alfa recipients (+4.3; 95%CI=2.3, 6.3) vs GT1/4 Lambda recipients (+0.4; 95%CI=-1.25, 2.0). Results were similar in GT2/3 patients.
BDII scores ≥20, which indicate moderate to severe depressive symptoms, were less frequent in the Lambda group (Table). CONCLUSIONS: Chronic HCV–infected GT1/4 patients treated with Lambda experienced fewer AEs related to the nervous system and fewer depressive symptoms vs patients treated with Alfa. Depression and psychiatric AEs will be
evaluated further in Lambda Phase 3 studies.
Association of Chronic Liver Disease with Depression: A Population-Based Study. M. Otgonsuren, M. Afendy, Z.M. , M. Otgonsuren, et al. ABSTRACT FINAL ID: 953
BACKGROUND: Chronic liver diseases (CLD) are associated with depression and other
neuropsychiatric disorders. AIM: The aim of this study was to assess the potential association of different types of CLD with depression in a population-based cohort. METHODS: We examined data from National Health and Nutrition Examination Survey (NHANES) for 2005-2010. We included adult patients (age over 18 years) with chronic hepatitis C or CH-C (HCV Antibody and HCV RNA-positive), chronic hepatitis B or CH-B (HBs-Antigen-positive), alcohol related liver disease or ALD (defined as >20 gram of alcohol consumption per day and elevated aminotransferases) and non-alcoholic fatty liver disease or NAFLD (defined as elevated aminotransferases in the absences of other liver diseases and excessive alcohol use). PHQ-9 survey was used as a depression screener. Univariate and multivariate analyses were performed to determine independent variables associated with each type of CLD and depression. Both SUDAAN® v.10.1 (Research Triangle Institute (RTI) International, Research Triangle Park, NC, USA) and SAS® v.9.3 (SAS Institute Incorporation, Cary, NC) were used for the analyses. RESULTS: The cohort included 15,263 participants. After multivariate analysis, CH-B was
independently associated with being Black (OR= 5.09, 95% CI: 2.41-10.76) or other races including being Hispanic (OR= 4.74, 95% CI: 2.32-9.70). On the other hand, ALD was independently associated with younger age (OR=0.97 95% CI:0.96-0.97), male gender (OR=0.82, 95% CI:0.74-0.91), but adversely associated being American-Mexican (OR=1.55, 95% CI: 1.30-1.84), and moderate to heavy smoking (OR=3.64, 95% CI: 3.09-4.30). furthermore, insulin resistance (OR=2.65, 95% CI: 1.98-3.55) and diabetes mellitus (OR=1.54, 95% CI: 1.11-2.13) were independently associated with NAFLD. CH-C was independently associated with age (OR=1.05, 95% CI: 1.03-1.07), male gender (OR=1.88, 95% CI: 1.19-2.97), black race (OR=2.50, 95% CI:1.50-4.18), smoking (OR=6.20, 95% CI: 1.62-23.68), injection drug use (OR=52.86, 95% CI:32.87-85.03) and depression (OR=2.87, 95% CI: 1.78-4.62). In fact, CH-C was the only type of CLD that was independently associated with depression. CONCLUSIONS: Although depression has been suspected to be associated with a number of liver diseases, this independent association is only with CH-C at the population level. This association remains strong even after adjustment for known risk factors for CH-C such as
intravenous drug use.
Determinants of Treatment Completion and Efficacy in Drug Users Assessed by Meta-analysis. R.B. Dimova, M. Zeremski, I.M. Jacobson, A. et al. ABSTRACT FINAL ID: 959
BACKGROUND: Hepatitis C virus (HCV)-infected drug users (DUs) have largely been excluded from HCV care. Whether exposure to services targeting DUs in HCV care affects the likelihood of completing therapy and achieving a sustained virological response (SVR) remains unclear. Therefore, we conducted a systematic review and meta-analysis of the available literature on treatment completion and SVR rates in DUs treated with pegylatedinterferon
(PEG-IFN)/ribavirin (RBV). We assessed effects of specific treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics.
METHODS: Studies that included at least 10 DUs treated with PEG-IFN/RBV and that reported treatment outcomes were analyzed. Each study was coded independently by two investigators. Homogeneity (I2) was assessed using Cochran’s test, and pooled rates estimated using random effects modeling. Meta-regression was used to analyze for sources of heterogeneity. RESULTS: Thirty-six studies including 2866 patients were retrieved, and 32 of them specified the rate of treatment completion. We estimated a pooled treatment completion rate among DUs of 83.4% (95% confidence interval [CI]: 77.1%; 88.9%), I2=90.2%, p<0.0001. When restricted to studies that included both addiction-treated and untreated patients during HCV therapy, we found that the higher the proportion of patients treated for addiction during HCV therapy, the higher the treatment completion rate (p<0.0001). We also identified a trend of increasing treatment
completion when the proportion of patients on substitution therapy at baseline increases (p=0.058). Further, we estimated a pooled SVR rate of 55.5% (95% CI: 50.6%; 60.3%). Infection with genotype 1/4 (p=0.0012) and the proportion of HIV co-infected DUs (p=0.0173) significantly influenced the SVR rate. Among genotype 1/4 patients, the SVR rate was estimated to be 44.9% (95% CI: 41.0%; 48.9%). Among studies with HCV mono-infected DUs, the SVR
rate was 58.1% (95% CI: 54.6%; 61.5%) and among studies including HIV/HCV co-infected DUs, the rate was 43.3% (95% CI: 35.9; 51.1).CONCLUSIONS: Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate for PEG-IFN/RBV-treated DUs is very similar to that obtained in registration trials conducted in the general population. Treatment of addiction during HCV therapy will likely continue to be important for HCV-infected DUs undergoing treatment with more complex regimens such as those containing direct acting antivirals.
Once Daily Sofosbuvir (GS-7977) Plus Ribavirin in Patients with HCV Genotypes 1, 2, and 3: The ELECTRON Trial. E.J. Gane, C.A. Stedman, R.H. Hyland, et al. ABSTRACT FINAL ID: 229
BACKGROUND: The first 5 arms of the ELECTRON trial showed that 12 wks of treatment with sofosbuvir (SOF, formerly GS-7977), a uridine nucleotide analog, plus ribavirin (RBV) is highly effective in treatment-naïve patients infected with genotype (GT) 2/3 hepatitis C virus (HCV). We report arms 7-11, designed to evaluate SOF + RBV in treatment-naïve and null responder GT 1 patients and treatment-experienced GT 2/3 patients (prior null response, breakthrough, or relapse), and to determine the feasibility of regimens with a shorter duration or reduced dose of RBV in treatment-naïve GT 2/3 patients. METHODS: 5 arms of non-cirrhotic HCV patients were enrolled. 3 arms received SOF + RBV (1000/1200 mg) × 12 wks: 10 GT 1 prior null responders (Arm 7), 25 treatment-naïve GT 1 patients (Arm 8); and 25 treatment-experienced GT 2/3 patients (Arm 9). In addition, 25 treatment-naïve GT 2/3 patients received SOF + RBV (1000/1200 mg) × 8 wks (Arm 10) and 10 treatment-naïve GT 2/3 patients received SOF + RBV (800 mg) × 12 wks (Arm 11). RESULTS: 95 patients were enrolled in the 5 arms. All 85 patients in Arms 7-10 achieved RVR. There were no ontreatment breakthroughs or discontinuations. Of the 25 treatment-naïve GT 1 patients, 22 (88%) achieved SVR4. Of
the 10 GT 1 prior null responders, 1 achieved SVR12; the other 9 relapsed prior to post-treatment wk 4. Of the 24 treatment-experienced GT 2/3 patients for whom data are available, 18 (75%) achieved SVR4. Two of these patients subsequently relapsed 8 wks after completing therapy for a total of 8 relapses on or before SVR8. To date, no S282Tcontaining mutations have been detected by either population or deep sequencing in any of the relapsers treated with
SOF + RBV. SOF + RBV was well tolerated in all arms and no patient discontinued early. Adverse events were generally mild and consistent with RBV treatment; no SAEs were attributed to SOF treatment. Grade 3/4 laboratory abnormalities were infrequent and generally consistent with RBV toxicity. SVR12 results for all arms will be presented. CONCLUSIONS: SOF + RBV elicited a rapid decline in HCV RNA in all treatment groups. All patients with Wk 4 data had RVR and no on-treatment viral breakthrough was observed. SOF + RBV for 12 wks provided high rates of SVR in treatment-naïve patients and in treatment-experienced GT 2/3 patients. Although all patients attained HCV RNA <LOD during treatment, GT 1 prior null responders had suboptimal rates of SVR. For those who failed the 12-week SOF + RBV regimen, either longer treatment duration or the addition of another DAA may be needed for these difficult-to treat populations, who have no currently approved treatment options.
Impact of baseline (BL) HCV RNA to predict treatment outcome in HCV genotype 2 and 3 patients receiving peginterferon (PegIFN) alfa-2a (40KD)/ribavirin (RBV): analysis of data from the multinational PROPHESYS cohorts. M.L. Shiffman, G. Parruti, P. Ferenci, et al. ABSTRACT FINAL ID: 787
BACKGROUND: PegIFN/RBV remains the standard of care for patients (pts) infected with HCV genotype (G)2 and 3. Pts treated with PegIFNα2a(40KD)/RBV who achieve a rapid virologic response (RVR) and have low BL HCV RNA can shorten treatment to 16 wks. Low viral load is not clearly defined but is often cited between 400,000 and 800,000IU/mL. This analysis explored whether an optimized virologic threshold could be identified to predict
treatment outcomes in HCV G2 and 3 pts prescribed PegIFNα2a (40KD)/RBV. METHODS: PROPHESYS comprised 3 separate, non-interventional cohort studies of pts receiving therapy for chronic hepatitis C according to country-specific requirements. This analysis included all treatment-naive, HCV mono-infected G2 (N=485) or 3 (N=591) pts with available BL HCV RNA results prescribed standard dosing of PegIFNα2a (40KD) and RBV. Receiver operating characteristics (ROC) curves and generalized additive models (GAM) were used to explore the relationship between BL HCV RNA level and treatment outcome (RVR and SVR, respectively).
RESULTS: Based on GAM plots, higher BL HCV RNA values were associated with a lower probability of RVR and SVR, though the association with SVR was stronger. Using ROC curves no optimized virologic threshold was identified that discriminated the likelihood of achieving an RVR. For SVR, thresholds of 600,000 and 1,200,000IU/mL were identified for HCV G2 and 3 pts respectively; however, these were only modestly better than selecting thresholds of 400,000 or 800,000IU/mL. Thus RVR and SVR rates for various thresholds of BL HCV RNA were estimated (Table). Overall, RVR was a strong predictor of SVR; in pts with an RVR, SVR rates were highest among pts with BL HCV RNA ≤400,000IU/mL and tended to decline with increasing BL HCV RNA. CONCLUSION: Although we identified thresholds predicting treatment outcome with PegIFNα2a (40KD)/RBV for HCV G2 or 3, they do not greatly improve the discrimination between high/low BL HCV RNA vs. traditional thresholds. Pts with
an RVR had a high probability of SVR, with SVR rates highest in those with BL HCV RNA ≤400,000IU/mL.
Clinical Depression and psychiatric events during HCV therapy withTelaprevir or Boceprevir. L. Pham, O. Mousa, C.I. Egwim, et al. ABSTRACT FINAL ID: 978
PURPOSE: Our aim is to evaluate the effect of the new Direct Acting Agents (DAA): Telaprevir (TVR) and Boceprevir (BVR), on the psychiatric health of hepatitis C patients. METHODS: We utilized the Beck Depression Inventory-II (BDI-II) to assess depression in our prospective cohort study of 110 HCV patients undergoing treatment with TVR or BVR, as part of the triple therapy of HCV at the Liver Associates of Texas Hepatology Clinics. The
patients attended an HCV education class and signed an informed consent before enrollment. Those who completed the survey during baseline scheduled visits and at a 4 week interval between 7/1/2011 and 5/31/2012 were eligible for interim statistical analysis. The endpoint is to study the effect of current DAAs on depression severity in Chronic HCV patients. SPSS v19 was used for statistical analysis and included descriptive statistics and regression analysis.
RESULTS: 110 patients receiving triple therapy were enrolled: 81 patients received TVR and 29 received BVR. Mean age 54.5 years (SD 7.89), mean body mass index 30.1 Kg/m2 (SD 6.47) and 48.2% are males. During scheduled clinic visits, the patients reported the feeling of depression in 32.9% of TVR patients, 24.1% of BVR patients and 35.1% of patients who discontinued therapy from any cause. The BDI-II conducted at week 12 showed Moderate to Extreme depression in 11.5% (3/26) of patients in the TVR group. Moderate depression was noticed in 50% (2/4) of the BVR group. 2 patients of the TVR group experienced extreme depression at week 4 (1/40) and at week 12 (1/26), while one patient in the BVR group experienced severe depression at week 8 (1/10). Percentage of patients with severe depression and suicidal ideation that led to treatment discontinuation was 1.2% (1/82) of TVR group vs 3.4% (1/29) of BVR group. There is no statistically significant difference in the depression severity at 12 weeks of therapy compared to baseline in patients treated with either TVR or BVR. No other psychiatric events that required hospitalization or medical therapy were reported. Other symptoms reported during therapy include Asthenia 32.4%, Insomnia 18%, Irritability 9% and Anxiety 5.4%. CONCLUSION: Mild Depression is commonly seen in patients being treated with triple therapy and does not lead to treatment discontinuation. Rates of severe and extreme depression weren’t significantly different among the two current DAAs.
First Report of Peginterferon Lambda/Ribavirin in Combination With Either Daclatasvir or Asunaprevir in HCV Genotype 1 Japanese Subjects: Early Sustained Virologic Response (SVR4) Results From the D-LITE Japanese Sub-Study. N. Izumi, M. LaTaillade, R. Scricca, D.S. et al. ABSTRACT FINAL ID: 234
BACKGROUND: Peginterferon lambda-1a (Lambda; type III interferon with limited extrahepatic receptor distribution) and direct acting antivirals (DAAs) are being developed for treatment of chronic hepatitis C. Lambda+RBV (L/R) combined with daclatasvir (DCV; first-in-class selective NS5A replication complex inhibitor) or asunaprevir (ASV; potent NS3 protease inhibitor) are evaluated in the phase 2b D-LITE study (AI452008) in HCV GT1. We report
sustained virologic response at posttreatment Week 4 (SVR4) in a prespecified D-LITE substudy in Japanese patients. METHODS: Treatment-naive patients were randomly assigned to L/R/DCV, L/R/ASV or peginterferon alfa-2a/R/placebo (A/R). L/R/DAA recipients with protocol-defined response (PDR+; Week (Wk) 4 HCV RNA <25 IU/mL, Wk12
undetectable [<10 IU/mL]) were treated for 24 wks. Those without PDR received a further 24 wks of L/R. All A/R recipients were treated for 48 wks. Lambda and alfa were dosed at 180μg QW; DCV 60mg QD; ASV 200mg BID; RBV weight-based BID. RESULTS: 21 patients were treated, all HCV GT1b. At this analysis, only DAA recipients with PDR (5/6 [83%] on
L/R/ASV [1 discontinuation Wk2 for LFT elevation], 8/8 [100%] on L/R/DCV) had posttreatment data through Wk4(Table). Two PDR+ patients in each arm had non-CC IL28B genotypes (2/5 [40%] L/R/ASV; 2/8 [25%] A/R/DCV); all achieved SVR4. L/R/DCV was better tolerated than L/R/ASV, with no SAEs, no AE-related discontinuations, and no Grade 3-4 transaminase or bilirubin elevations in the L/R/DCV arm. CONCLUSIONS: Lambda/R-based regimens with ASV or DCV were highly effective in Japanese patients. 83% and 100%, respectively, achieved PDR, all of whom subsequently achieved SVR4. L/R/DCV was better tolerated than L/R/ASV. Among Japanese patients with HCV GT1b, L/R/DCV demonstrated rapid and early sustained virologic response and was very well-tolerated.
Hemoglobin Decline >2 g/dL During Peginterferon Alfa-2b (Peg-2b)/ Ribavirin (RBV) Treatment Predicts Favorable SVR in Patients with HCV Genotype 1 and HCV Genotype 2/3 Infection Without Erythropoietin Use. G. Teuber, S. Mauss,D. Hueppe, et al. ABSTRACT FINAL ID: 789
BACKGROUND: It has been shown that anemia and the hemoglobin (Hb) decline during Peg2b/RBV treatment of genotype 1 (G1) infection predict favorable SVR rates (Sulkowski M, Gastroenterology 2010). However, approximately 50% of the patients (pts) with anemia received erythropoietin, which may have confounded the association between Hb decline and SVR. We here investigated whether the association between Hb decline and SVR can be confirmed for pts treated for HCV G1 and for HCV G2/3 infection in real-life without erythropoietin treatment for anemia. METHODS: Data of pts treated for chronic hepatitis C within the German Peg2b/RBV observational study were retrospectively analyzed. Pts were treated with Peg2b 1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks. RESULTS: 1851 pts with G1 infection had baseline and at least one Hb measurement during therapy. Overall SVR rate was 42.6% (789/1851). A significant (p=0.0004) difference in SVR rates was obtained by comparing pts with Hb declines >2 g/dL (44.6%, 673/1510) with those who experienced Hb declines ≤2 g/dL (34.0%, 116/341). Hb declines >2 g/dl were significantly associated with higher SVR rates in difficult-to-treat G1 pts, such as pts elder than 50 years or with high baseline viral load (Table). Similar results were obtained for 1308 pts treated for HCV G2/3 infection. Again, pts with Hb declines > 2g/dl achieved significantly higher SVR rates (71.3%) than pts with Hb declines ≤2 g/dL (62.1%). In this study only one patient with G1 infection received erythropoietin treatment for anemia. CONCLUSIONS: Patients treated for HCV G1 and G2/3 infection in real-life achieve up to 15% higher SVR rates when they develop a Hb decline >2 g/dL during Peg2b/RBV treatment. This beneficial effect is unrelated to erythropoietin use.
Rapid and early virologic response to Cepeginterferon-alfa-2b in combination with ribavirine in treatment-naïve patients with chronic HCV. O. Znoyko, E. Klimova, S. Maximov, et al. ABSTRACT FINAL ID: 807
BACKGROUND: Cepeginterferon-alfa-2b is a new pegylated interferon-alfa (IFN-α) molecule consisting of linear polyethylene glycol (PEG) (molecular weight 20 kDa) linked to IFN-alfa strictly at one site through N-terminal cysteine amino group. 1.5 and 2.0 μg/kg weekly doses of cepeginterferon-alfa-2b were selected for further studies in HCV-infected patients based on esults of Phase I study. METHODS: Multicenter open-label randomized prospective phase II study of efficacy and safety of cepeginterferon-alfa-2b in comparison with peginterferon-alfa-2b within combination therapy of hepatitis C. 150 treatment-naïve patients with genotype 1, 2, and 3 HCV were randomized into 3 groups: cepeginterferon-alfa-2b 1.5 μg/kg weekly,
cepeginterferon-alfa-2b 2.0 μg/kg weekly, and a reference group of peginterferon-alfa-α2b 1.5 μg/kg weekly in combination with ribavirine 800-1400 mg/day. RESULTS: In patients with HCV genotype 2 and 3, rapid and early virologic response (RNA HCV level below the
detection limit of 15 IE/mL or ≥ 2log10 decrease of viral load after 4 or 12 weeks of treatment) were achieved in 100% of patients in all treatment groups (per protocol analysis). In patients with HCV genotype 1, rapid virologic response was observed in 66.7% and 77.8% of patients receiving cepeginterferon-alfa-2b 1.5 and 2.0 μg/kg weekly vs. 75% in the group of peginterferon-alfa-α2b 1.5 μg/kg weekly (p>0.05 for all treatment groups). After 12 weeks of treatment, early virologic response was recorded in 92.3% and 96% vs. 84% of patients, correspondingly (p>0.05 for all treatment groups). Safety profiles of investigational products were similar. Administration of cepeginterferon alfa-2b 2.0 μg/kg weekly was associated with a higher incidence of adverse effects requiring dose adjustment in comparison to cepeginterferon-alfa- 2b or peginterferon-alfa-α2b 1.5 μg/kg weekly. CONCLUSIONS: Cepeginterferon-alfa-2b is at least non-inferior to peginterferon-alfa-α2b in regard to frequency of rapid and early virologic response. Overall, adverse events occurring during the treatment with cepeginterferon-alfa-2b are dose-dependent; however, their frequency is no more than in patients receiving standard doses of peginterferon-alfa- α2b.
Age- and Gender-Related Differences in SVR and Relapse Following Treatment of HCV Genotype 3 (G3) Infection with Peginterferon Alfa-2b (Peg2b)/Ribavirin (RBV) in Real-Life. S. Mauss|D. Hueppe, E. Zehnter, et al. ABSTRACT FINAL ID: 812
BACKGROUND: Because of the current lack of direct antiviral drugs, improvement of HCV G3 treatment can be achieved only by optimization of dual therapy. Preliminary data suggest lower SVR rates for G3 infected elder patients. We therefore aimed to identify the contributing factors. METHODS: Within a multicenter observational study in Germany 1328 of 4061 patients with chronic hepatitis C were infected with G3. Of these, 1090 patients had documented treatment with Peg-IFNα-2b 1.5 μg/kg/wk plus RBV (800-1200 mg/day) for a median of 24 weeks and were included in this retrospective analysis. Patients were stratified according to baseline viral load, age, gender and platelet count. RESULTS: A SVR rate of 66.3% (723/1090) was observed in the overall G3 population. SVR rates of 66.7% (371/556) and 66.6% (321/482) were not different in patients with low (<600.000 IU/ml) and high (≥600.000 IU/ml) baseline viral load. Patients ≥ 40 years achieved significantly (p=0.0002) lower SVR rates (59.5%, 245/412) than patients < 40 years (70.5%, 478/678). This was related to a marked increase of relapse rates from 7.9 to 23.4% in elder patients while non-response rates remained comparable (6.8 vs 10.7%). The decline in SVR was most prominent in male patients ≥40 years and accompanied by significantly higher relapse rates compared to female patients [Table]. In addition, there was a 2-fold higher proportion of low baseline platelet count <150 n/L in the male population suggesting that advanced fibrosis could in part contribute to the differences between female and male patients. CONCLUSIONS: In G3 patients older age affects SVR pre-dominantly in male patients by higher relapse rates and not by primary non-response. In contrast to previous reports premenopausal women due not have higher SVR rates compared to men. The effect of age on relapse may be overcome by prolonged therapy and should stimulatein individualized treatment strategies in older patients with G3 infection.
High Early Response Rates with Protease Inhibitor Triple Therapy in a Multicenter Cohort of HCV-Infected Patients Awaiting Liver Transplantation. E.C. Verna, T. Lukose, S.K. Olsen, et al. ABSTRACT FINAL ID: 52
BACKGROUND: Hepatitis C Virus (HCV) is a leading indication for liver transplant (LT), and recurrent HCV diminishes post-LT survival. HCV treatment with peginterferon (PEG) and ribavirin (RBV) pre-LT is limited by poor tolerability and efficacy, but can prevent recurrent HCV if virologic response (VR) is achieved. The addition of a protease inhibitor (PI) to PEG/RBV increases VR rates in genotype 1 (G1) HCV, however safety and efficacy data in
patients awaiting LT are lacking. METHODS: Consecutive PI-treated patients with G1 HCV awaiting LT (listed or in evaluation) from 2 centers were assessed. HCV RNA undetectability (<LOD) at weeks 4 and 12 and safety were the primary endpoints. The majority (90%) was treated with telaprevir as PI. 25% had a PEG/RBV lead-in (LI) for a median of 31 days, 30% had SBP prophylaxis, and 40% growth factors. RESULTS: 20 patients (median age 59, 75%
male, 10% Hispanic, 10% Black) have been treated for a median (range) of 14 (9-21) weeks, including LI. 65% were previously treated (69% null/partial, 31% relapsers). At initiation, median (range) laboratory and UNOS MELD were 8 (6-16) and 9 (7-31), respectively; 9 (45%) had hepatocellular carcinoma with UNOS exception. 20% each had a history of ascites or encephalopathy. Median (IQR) HCV RNA pre-treatment was 6.08 log IU/ml (5.72-6.45). 90% and 70% of patients completed 4 and 12 weeks of PI therapy, respectively. At week 4 of PI, 8/18 (44%) were <LOD, 3/18 (17%) were detected but unquantifiable (<LOQ), and 7 (39%) were >LOQ. At week 12 of PI, 10/14 (71%) were <LOD, 2/14 (14%) were <LOQ and 2/14 (14%) were >LOQ. The median (IQR) decline in viral load at 4 and 12 weeks of PI were 6.11 log IU/ml (5.74-6.60) and 6.20 log IU/ml (5.74-6.66), respectively. Median (range) days from PI initiation to <LOD was 28 (14-109), among the 13 achieving it. No viral breakthrough occurred. Early discontinuation occurred in 5 (25%) patients (1 non-response, 1 rash, 1 optic neuritis, 2 liver decompensation). Neither patient with decompensation received LI or SBP prophylaxis, and one underwent LT at week 3 and remains <LOD 3 weeks post-LT. Overall, 2 (10%) had SAEs with hospitalization, but none died, required transfusion, or had significant renal failure. CONCLU-SIONS: A high rate of early on-treatment VR is possible with triple therapy in patients awaiting LT, despite advanced fibrosis, high viral loads and a high rate of prior non-response. However, caution is needed as early discontinuation was common and 10% of patients decompensated. Longer follow-up is needed, but VR maintained for even short periods prior to LT might prevent recurrent HCV and further study of this approach is warranted.
Cannabinoid Receptor 2 (CB2) Q63 Variant in Chronic Hepatitis C: An Association with a More Severe Hepatocellular Necrosis. N. Coppola, M. Macera, M. Pisaturo, et al. ABSTRACT FINAL ID: 186
AIMS: to evaluate in patients with chronic hepatitis C the clinical impact of the rs357661398 single nucleotide polymorphism (SNP) of the CNR2 gene leading to the substitution of the Arg (R) of codon 63 of the Cannabinoid Receptor 2 (CB2) with a Gln (Q). PATIENTS AND METHODS: 169 consecutive anti-HCV/HCV-RNA positive patients (HCV group) were enrolled from April 2007 to December 2011 at the time of their first liver biopsy: males 59.1%; median age 53 years (range 18-80), median serum HCV-RNA 9x10E5 IU/ml (range 200-6.5x10E7), 70.4% with genotype 1. A control group of 51 consecutive patients with chronic hepatitis B (HBV group) who underwent their first liver biopsy in the same period was established: males 68.6%; median age 47 years (range 27-69); median serum HBV-DNA 1.5x10E5 IU/ml (range 150-1.1x10E7); all HBV genotype D and anti-HBe positive. All patients in the study were naive to antiviral therapy and were screened for the CNR2 rs357661398 SNP by direct sequencing. RESULTS: The prevalence of patients with CB2-63 QQ variant was similar in the two groups (10.7% and 9.8%). CB2-63 RR variant was more frequently identified in patients in HBV group than in those in HCV group (47.1% vs 27.2%, p<0.05), while CB2-63 RQ in HCV group than in those in HBV group (62.1% vs. 43.1%, p<0.05). Regarding HCV group, patients with CB2-63 QQ variant showed higher aminotransferase serum levels and higher score of Histological Activity Index (HAI) (Table 1); the logistic regression analysis identified CB2-63 QQ variant and fibrosis score as the only independent predictors of a more severe HAI (>8) (p <0.0001). DISCUSSION: The homozygosis for CB2 Q63 variant is more frequent in HBV than in HCV patients. In chronic hepatitis C this variant predict a more severe hepatocellular necrosis.
IL28B rs12979860 CC Genotype, Metabolic Profile and SVR in Patients with Genotype 1 Chronic Hepatitis C. S. Petta, S. Grimaudo, C. Cammà, et al ABSTRACT FINAL ID: 1016
BACKGROUND AND AIMS: Patients with genotype 1 chronic hepatitis C (G1-CHC) frequently display steatosis and insulin resistance (IR), due to both metabolic and viral factors. Clinically, this translates to accelerated liver disease progression and a reduced response to therapy. Sustained virological response (SVR) in G1-CHC is also strongly associated with olymorphisms near the IL28B gene, but the interaction between IL28B genotype and insulin resistance and their combine effects of SVR has not been defined. We tested the association between the IL28B rs12979860 genotype and metabolic features, including IR, and evaluated their relative impact on SVR. METHODS: Four hundreds and thirty-four G1-CHC consecutively biopsied patients in three tertiary centers were genotyped for the IL28B rs12979860 SNP. Their metabolic profile included assessment of lipid levels and insulin resistance (IR) by the homeostasis model assessment (HOMA-IR). RESULTS: IL28B CC patients had higher levels of total and LDL cholesterol, lower triglycerides, and a lower prevalence of both IR and moderate-severe steatosis (p<0.05). By multiple logistic regression analysis, BMI (OR 1.223, p<0.001), triglycerides (OR 1.007, p=0.006), IL28B CC (OR 0.378, p=0.001) and HCVRNA >850000UI (OR 1.803, p=0.01) were independently associated with IR. IL28B CC (OR 8.350, p<0.001) and IR (OR 0.432, p=0.005), but not steatosis (OR 0.582, p=0.25), were independently associated with SVR. See later re strengthening this if we can show an interaction. CONCLUSIONS: In G1-CHC patients the IL28B rs12979860 CC genotype is associated with reduced insulin resistance independent of the classical risk factors. Both IL28B rs12979860 genotype and HOMA-IR additively and interactively strongly influence the outcome of antiviral therapy.
Interferon-λ3 determines response to pegylated interfern/ribvirin therpy in chronic hepatitis C patients. K. Murata, M. Sugiyama, Y. Aoki, et al ABSTRACT FINAL ID: 1021
BACKGROUND & AIMS: We identified single nucleotide polymorphisms (SNP) associated with interleukin-28B gene (IL28B), encoding IFN-λ3, as predicting factors for non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy by genome-wide association study (GWAS) in Japanese patients with chronic hepatitis C (CHC)(Tanaka Y, Mizokami M, et al. Nat genet 2009). However, the genetic variation of IL28B failed to predict the treatment response at about 20%. Therefore, we investigated IFN-λs production in peripheral blood mononuclear cells (PBMCs) and analyzed its association with genetic variations in IL28B and responses to treatment. METHODS: Message and protein levels of IFN-λs induced by ex vivo stimulation of PBMC with IFN-α, following stimulation with toll-like receptor (TLR) agonists (TLR3; Poly I:C, TLR7; R-837), as measured by quantitative real-time polymerase chain reaction (PCR) and our newly developed enzyme-linked immnosorbent assay (Sugiyama M, Murata K, et al. Hepatol Res 2012), were compared with clinical data. All subjects were evaluated for SNP near IL28B (rs8099917, rs12979860). Non-invasive evaluation of liver fibrosis was done by acoustic radiation force impulse (ARFI) elastography. RESULTS: In most cases, both SNPs were in linkage disequilibrium, and rs8099917 was better associated with the therapeutic response. Therefore, we used rs8099917 for following analysis (TT is considered as predictive factor for a favorable response to Peg-IFN/RBV whereas TG/GG is for an unfavorable response). R-837 along with IFN-α induced IFN-λs, whereas poly I:C failed the prominent induction in both healthy volunteers (n=12) and CHC patients (n=94). In CHC patients with TT genotype, IFN-λ3 was more robustly upregulated by R-837 than those with TG/GG, whereas no significances were observed in IFN-λ1, IFN-λ2. Importantly, IFN-λ3 production determined the response (transient responder vs non-responder) in CHC patients with genotype 1b who had previously failed Peg-IFN/RBV treatment (n=41), regardless of IL28B genotypes (p=4.0×10-9). Our method more accurately predicted treatment efficacies at 97.6% than did IL28B genotyping (63.4%). Based on multivariate logistic analysis, treatment failure in patients with TT genotype was associated with high sheared wave velocity by ARFI, implicating the mechanism of non-responsiveness to Peg-IFN/RBV therapy in advanced liver fibrosis. CONCLUSIONS: Genetic or post-transcriptional regulations of IFN-λ3 have key roles for the response to Peg-IFN/RBV therapy, which supported our GWAS data. Our method could provide more accurate prediction for the efficacy of Peg-IFN/RBV therapy than genetic analysis.
HCV infection of human stem cell-derived hepatocytes and potential strategy for treatment of viral liver diseases. A. Carpentier, Q. Li, F. Zhang, et al ABSTRACT FINAL ID: 1290
Treatment for hepatitis C has improved but many patients do not respond to current therapy.
Accumulating evidence indicate that patient specific factors significantly affect the response to antiviral treatments. However, in vitro models recapitulating hepatitis C virus (HCV) infection in the context of the patient specific genetic background are missing. Generation of patient specific induced pluripotent stem cells (iPSC) and the technology to developmentally program these cells to hepatic lineage offer great promise. In this context, we hypothesize that this approach could be useful in developing a relevant personalized model for HCV infection in vitro. Moreover, the iPSCs approach could allow the generation of autologous patient-specific hepatocytes with promising opportunity for cell therapy of viral liver diseases. We generated iPSCs from primary fibroblasts using lentiviral vectors, and characterized them in comparison to embryonic stem cells. Human pluripotent stem cells were efficiently differentiated into hepatocyte like cells (HLC), as demonstrated by induction of hepatic genes and secretion of hepatic proteins (AFP and albumin) in the supernatant. Moreover these cells recapitulate hepatocyte-specific metabolic functions like lipid and glycogen accumulation, and indocyanin green metabolism. These HLC were subsequently infected with HCV. During the first week post-infection, increasing level of intracellular HCV RNA could be detected in these cells, confirming entry of the virus and replication of the viral genome. Infection of HLC were further confirmed by hepatitis C dependent fluorescence relocalization assay. Moreover, we assessed HCV RNA, core protein and infectivity in the supernatant, confirming the production of infectious virus by HCV-infected HLC. These infected cells also respond to antiviral therapy, such as interferon-α and 2'-methylcytidine, a nucleoside analog inhibitor of HCV polymerase. Interestingly, HCV infection also induces intrinsic innate immune response including interferon response, as previously described in infected primary human hepatocytes. In conclusion, we demonstrated that HLC derived from patient pluripotent stem cells support infection by HCV. This approach constitutes a unique tool to analyze the induction of innate immunity in response to HCV infection and antiviral treatment in the context of the patient's genetic background. Moreover, by targeting proviral cellular factors or introducing antiviral factors in these cells, we hope to generate HCV resistant-patient specific-hepatocytes. This approach holds promises for cell therapy of hepatitis C, particularly for patients with end-stage liver diseases.
Il28b polymorphism, rs12979860, determines the activity of liver lymphocytes. A. Marlu, V. Leroy, J.H. Zarski, et al ABSTRACT FINAL ID: 181
Polymorphism of IL28B is correlated with a sustained virological response (SVR) in Hepatitis C Virus (HCV) infected patients treated with Pegylated Interferon-α combined with Ribavirin. The single nucleotide polymorphism (rs12979860), located near the IL28B gene, defines two alleles C/T, C allele being associated to SVR.However, the effect of this polymorphism on immune functions of the liver, the site of HCV production, and the mechanism of SVR remain still unknown. Chronically HCV-infected genotype 1 patients were genotyped for IL28B rs12979860. Liver samples were collected from the needle biopsy prior treatment. Single cell suspensions were prepared by mechanical disruption. Liver lymphocytes (T, Treg, NK and NKT) were identified by flow cytometry for the expression of CD45, CD3, CD4, CD8,CD56 and FoxP3 as markers and CD107a for degranulation activity. Immunohistochemistry were performed on in paraffin sections for the detection of CD8 and FoxP3. Statistical analysis was done with Mann-Whitney "U" test and Wilcoxon matched-t test. Lymphocytes from 52 fresh liver biopsies displayed similar distributions of T (CD3), NKT (CD3, CD56) and NK (CD56)among CD45 cells, whatever the IL28B genotype of the patients. Strikingly, higher degranulation activity, revealed by CD107a surface expression, was observed in T (p=0.000), NKT (p=0.002) and NK cells (p=0.015) of patients with CC genotype (n=17) compared to patients with CT or TT genotypes (n=35); patients with CC genotype displayed two fold higher degranulation activity than patients with CT genotype in T (p=0.001), NKT (p=0.002) and NK cells (p=0.011); no significant difference was observed between patients with CT and TT genotypes. Sections of liver from 19 patients showed the frequency of CD4-FoxP3 lymphocytes two fold higher (p=0.004) in patients with CC genotype (n=11) as compared to patients with CT genotype (n=8) supporting the presence of Treg.Ratio between the number of CD8 cells and FoxP3 cells in parenchymatous necro-inflammatory areas was maintained in the early stage of the chronic hepatitis only in patients with CC genotype, whereas this ratio was reduced in patients with CT genotype due to lower number of FoxP3 cells.These data provide new insights into the role of IL28B polymorphism related to SVR in treatment of HCV genotype 1 infected patients. CC genotype, which is linked to a good response to therapy, is associated to higher efficiency of effector lymphocytes (T, NK and NKT) of the liver. The liver immune response appears tightly regulated as suggested by the links between CD8 cells and CD4-FoxP3 cells.
Identification of Interferon Effector Genes as New Targets for HCV Antiviral Develop-ment. D.N. Fusco, C. Brisac, E.A. Schaefer, et al. ABSTRACT FINAL ID: 1031
PURPOSE: The mechanisms underlying antiviral effects of interferon-alpha (IFN-a) have not been completely elucidated due to a lack of tools to systematically evaluate the hundreds of IFN stimulated genes (ISGs) and technical challenges related to study of hepatitis C virus (HCV). To identify IFN-regulated modulators of HCV infection, we developed an HCV replicon-based high-throughput screening assay for use with RNA interference libraries (Tai AW,et al. Cell Host Microbe. 2009;5:298-307), followed by an image based screening platform using fully infectious JFH1 HCV that enables study of the entire HCV lifecycle (Li Q, et al. PNAS,. 2009;106:16410-5). We have optimized a platform for high throughput image-based RNAi screening for host factors involved in the IFN response to fully infectious HCV (JFH1). Using this platform, we performed a whole genome siRNA screen for anti-HCV interferon effector genes (IEGs). METHODS: Huh 7.5.1 hepatocytes are transfected with siRNA. Two days later, cells are treated with IFNa. One day later, cells are inoculated with JFH1 HCV. Two days post-infection, cells are stained with HCV core antibody and Hoechst nuclear stain, then imaged using an automated microscope to determine the percent infected cells. Rescue from IFN treatment is scored as a 2-fold increase in percent infection above plate mean. Our positive control for IFN rescue, IFNa receptor 1 (IFNAR), rescues ~50% of HCV replication from IFNa suppression, and our negative control,non-targeting (NT3), does not rescue HCV from IFN compared to plate mean. RESULTS: We identified several known HCV ISGs (eg TYK2, ISGF3G) as well as previously unknown IEGs, including P285, ALG10, and MYST1. The siRNAs used to silence these genes were validated for mRNA knockdown. IFN stimulation analysis revealed that P285 is upregulated at the mRNA level by IFN alpha and lambda, but ALG10 and MYST1 are not, In addition, these genes appear to rescue HCV from IFN at one or more steps of the HCV lifecycle.
CONCLUSION: This powerful approach makes it possible to identify in an unbiased manner host genes that regulate HCV containment by IFN and, by extension, fail in patient populations with high rates of persistence. It appears that multiple effectors of the IFN response (IEGs) are not upregulated at the mRNA level by IFN, and thus compose a distinct class of non-ISG IEGs. These IEGs may inform design of novel antiviral drugs.
miRNAs involved in insulin resistance are regulated in vitro by HCV infection. M. García-Valdecasas, A. Rojas, L.A. Rojas, et al. ABSTRACT FINAL ID: 1086
BACKGROUND AND AIMS: The hepatitis C virus induces insulin resistance and steatosis, but the molecular mechanisms involved in these processes are not yet completely understood. PTEN is an inhibitor of PI3K protein which plays an essential role in the insulin signaling pathway. PTEN is down-regulated in infected cells. The aim of this work is to analyze the mechanism in which JFH1 interacts with PTEN and PI3K, and with others downstream proteins of the insulin signaling pathway,studying the expression of miRNAs targeting PTEN (miRNA29a and b), and the role of a PI3K inhibitor (LY294002) in viral replication. METHODS: Huh7.5 cells were grown and infected with the JFH1 replicon (1 particle/cell). LY294002 (10μM) or insulin (10nM)were added to the cells. Total RNA extraction was performed 48 hours after the media was changed. The expression of the different genes was quantified using the qRT-PCR Quantace (Bioline) kit and analysis of specific proteins analyzed by Western-Blot. miRNA expression was quantified using the miScripReverseTranscription and miScript SYBR®Green commercial Kits (Quiagen). RESULTS: Huh7.5 cells infected with JFH1 showed decreased PTEN and PI3K protein levels. In cells infected and with hyper-insulinemia, PTEN was further decreased whereas PI3K showed no difference compared to control experiments. When Huh7.5 cells were treated with the PI3K inhibitor LY294002, gene expression of PI3K was increased in control 1.6 (±0.3) and in virus 2.6 (±0.9) fold induction respectively, likely due to a feed-back cellular response. AKT and mTOR, downstream proteins of the PI3K pathway, are increased in control and infected cells treated with LY294002 (AKT: 1.7±0.7 vs. 1.6±0.01 fold induction; mTOR: 1.5±0.1 vs. 2.6±0.8 fold induction). Other proteins of the insulin signaling pathway PTEN4, PTP1B and PTP2 showed increased gene expression. LY294002 inhibitor did not affect significantly viral replication rates (decreasing by 20% compared to α-interferon). miRNA29a and 29b (targeting PTEN), were increased 1.5 (±0.01) and 2.1 (±0.1) fold induction in cells infected with JFH1. CONCLUSION: PI3K inhibitor LY294002 modulates gene expression and slightly decreases viral replication, probably due to inhibition of IRS1 phosphorylation. miRNA29a and 29b induction could explain the reduction of PTEN levels and seems to be a link between HCV infection and metabolic disorders.
Effect of Chronic Hepatitis C Virus Infection on Bone Mineral Density. J. Lin, T. Hsieh, P. Chen, et al. ABSTRACT FINAL ID: 987
PURPOSE: Whether chronic hepatitis C virus (HCV) infection is a risk factor for the develop-ment of bone disease has long been controversial. For this reason, we conducted a thorough investigation of bone turnover markers and bone mineral density (BMD) in a homogenous cohort of patients with non-cirrhotic chronic HCV infection. METHODS: Chronic HCV-infected participants (n = 69) were recruited into a prospective cohort study and underwent dual- energy X-ray absorptiometry for determination of BMD. Fibrosis staging was evaluated according to the noninvasive index FIB-4. T-scores at the femoral neck and lumbar spine were used as the primary outcome variables to assess the association between degree of liver fibrosis and BMD. Osteoporosis was defined as a T-score ≦ -2.5, and osteopenia as a T-score between -1.0 and -2.5. RESULTS: The population was 41% male with a mean age of 53.6 years. The mean BMD, Z-score, and T-score values of lumbar spine in chronic hepatitis C (CHC) patients were significantly lower than those in healthy controls (p <0.001). The rate of osteoporosis for CHC patients between 45 and 54 years was significantly higher than that of the control group (p = 0.011). Bone alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen levels were also significantly higher in the reduced BMD population. Patients with more advanced liver fibrosis had significantly lower BMD (Table). CONCLUSION: Reduced BMD is common in this population of chronic HCV-infected patients, by increased bone turnover in the osteodystrophy pathogenesis, probably associated with liver disease severity.
Treatment of Chronic Hepatitis C Improves Clinical Outcomes Despite Lack of Achievement of Sustained Virological Response in HIV-HCV Coinfected Patients with Advanced Liver Fibrosis. P. Labarga, J. Fernández-Montero, F. Rick, E. et al. ABSTRACT FINAL ID: 988
BACKGROUND: HCV clearance following hepatitis C therapy is associated with significant reductions in liver-related complications and death. A potential benefit of hepatitis C therapy in the absence of achievement of SVR has been pointed out occasionally. This information could be particularly relevant in HIV/HCV-coinfected patients, in whom treatment response is lower and liver disease occurs faster. METHODS: Retrospective study of clinical end-points in a large cohort of HIV/HCV-coinfected patients who had longitudinal assessment of liver fibrosis by elastometry (FibroScan). Follow-up ended at the time of last visit, first liver decompensation event or death. Patients were split out into two groups, failures to peginterferon/ribavirin and never treated patients. Liver fibrosis progression was defined as a shift from Metavir estimates ≤F2 to F3-F4, or by >30% increase in liver stiffness values in patients with baseline Metavir estimates of F3-F4. RESULTS: A total of 389 patients were analyzed, 201 (52%) treatment failures and 188 (48%) never treated. The main characteristics of these two groups were comparable (mean age 41 years-old, 72% males, 86% former IDUs, 92% on HAART, mean CD4 count >450 cells/uL, mean HCV-RNA 5.5 log IU/mL). Differences between treated and untreated patients were noticed for the proportion of HCV genotypes 1/4 (90% vs 81%, p=0.008), baseline Metavir F3-F4 (44% vs 26%, p<0.001), HBsAg+ (2.4% vs 7.6%, p=0.02) and alcohol abuse (9.2% vs 15.3%, p=0.08).After a median follow-up of 68 months, treated versus untreated patients experienced similar liver fibrosis progression (26% vs 20%, p=0.1), liver decompensation events (12% vs 13%, p=0.6), and deaths (2% vs 0%, p=0.1). However, in
the subset of patients with baseline Metavir F3-F4, liver decompensation events or deaths occurred less frequently in treated than untreated patients (19% vs 42%, p=0.005). This finding was confirmed after adjusting for baseline haemoglobin, platelets or CD4 counts. A Cox regression analysis in the whole population confirmed that baseline Metavir F3-F4 was the only predictor of liver decompensation events or death in this population. CONCLUSIONS: Treatment of chronic hepatitis C is associated with a reduced incidence of liver complications and death in HIV-infected patients with advanced liver fibrosis. This benefit might result from an anti-inflammatory effect of therapy and/or a better socio-clinical profile of treated than untreated patients.
Differences in CD4+ and CD8+ Memory T-cell Expression in HIV, Hepatitis C (HCV), and HIV/HCV Coinfection are Influenced by HIV and HCV Infection Status. A. Hodowanec, S. Kincaid, M. Bahk, G. et al. ABSTRACT FINAL ID: 1055
BACKGROUND: Increased immune activation with dysregulated T-cell mediated immune responses may be associated with accelerated liver fibrosis in HIV/HCV-coinfected patients. Differences in CD4 and CD8 T-cell subset expression in patients with HIV-monoinfection, HCV-monoinfection, and HIV/HCV-coinfection have not been fully explored. METHODS: Fifty-nine age (median, 53 years) and sex (male=43/female=16)-matched patients were stratified: A) HIVmonoinfection (N=15), B) HCV-monoinfection with chronic hepatitis C (CHC) (N=15), C) HIV/HCV-coinfection with CHC (N=14), and D) HIV/HCV-seropositive with cleared HCV (N=15). All HIV+ patients had undetectable HIV RNA, and current CD4 counts in strata A and C were matched to CD4 at estimated time point of HCV clearance in strata D (median, CD4=420 cells/ml). The estimated median duration of HCV infection among strata B, C, and D was 26 years (range, 3-40 years). Sociodemographic data and liver- and HIV-related laboratory results were recorded and cells collected for CD4 and CD8 naïve T-cell (CD45RA+CCR7+), central memory T-cell (CD45RA-CCR7+), terminal effectors expressing RA (TEMRA) T-cell (CD45RA+CCR7-), and effector memory T-cell (CD45RA-CCR7-) measurement via flow cytometry. All subjects underwent transient elastography to stage liver fibrosis. Immune
markers were analyzed in multivariate models across strata using pair-wise t-tests. RESULTS: Mean CD4 central memory T-cell expression was greater among HCV-monoinfected patients (24%) than HIV-monoinfected patients (18%)(p=0.018), HIV/HCV-coinfected patients with CHC (20%)(p=0.014), and HIV/HCVcoinfected patients with cleared HCV (18%)(p=0.003). CD8 central memory T-cell expression was also greater in HCV-monoinfection (12%) than HIV-monoinfection (6%)(p=0.033) and HIV/HCV-coinfection with cleared HCV (5%)(p=0.001). Conversely, CD4 TEMRA T-cell expression was lower in HCV-monoinfection (7%) versus HIVmonoinfection (17%)(p=0.006) and HIV/HCV-coinfection with cleared HCV infection (16%)(p=0.007). There was no significant difference in CD4 or CD8 naïve T-cell or effector memory T-cell expression across strata. Overall, advanced fibrosis was associated with lower CD8 central memory (p=0.027) and higher CD8 TEMRA (p=0.003) T-cell expression. CONCLUSIONS: HCV-monoinfection appears to be associated with a greater reserve of central memory cells that may limit terminal effector activity in patients with longstanding chronic HCV infection. These findings may reflect a relative quiescent immune environment in HCV-monoinfection compared to concurrent HIV infection, in which increased
immune activation may contribute to accelerated rates of liver fibrosis.
Individuals coinfected with human immunodeficiency virus and hepatitis C virus are at increased risk of reduced bone mineral density and bone fracture: a systematic review.
L. Rivera, H. Thein, ABSTRACT FINAL ID: 972
The prevalence of chronic viral hepatitis infection is a concern for HIV-infected individuals in the era of highly active antiretroviral therapy. We aimed to examine whether coinfection with HIV and hepatitis C virus (HCV) in adults is associated with low bone mineral density (BMD) or an increased risk of bone fracture compared to either monoinfected or uninfected individuals. We performed a systematic literature review in May 2012 of studies published since 1980. Studies reporting BMD or bone fracture as a powered outcome and a measure of association between
HIV/HCV coinfection and either outcome were included. Baseline risk factor data were extracted. Ten studies met the inclusion criteria, with 4 cross-sectional studies examining low BMD and 5 studies (1 case-control, 5 longitudinal) examining bone fracture. The majority of coinfected patients were antiretroviral-treated. Four studies compared low BMD between HIV/HCV coinfected individuals (n=729) and HIV monoinfected (n=966) or uninfected controls (n=224) and showed that the odds of reduced BMD was 45% greater in the coinfected individuals than the controls (pooled OR=1.45, 95% CI=1.13-1.88). Studies examining bone fracture in coinfected individuals compared to controls were heterogeneous in the measures of association chosen to report this comparison; results were pooled where possible. Pooling three studies that reported the odds of experiencing bone fracture indicated that the odds of coinfected
individuals (n=1,686) experiencing fracture is 145% greater than monoinfected (n=9,507) or uninfected (n=26,652) controls (pooled OR=2.45, 95% CI=1.97-3.03). Two studies reported incidence rate ratios. Pooling these, fracture incidence rate in the coinfected individuals (n=851) was 2.92 times (95% CI=2.52-3.39) the incidence rate experienced by monoinfected (n=5,736) or uninfected controls (n=26,530). Finally, pooling hazard ratios for fracture generated by 3 studies indicated that the hazard of fracture experienced by coinfected patients (n=38,207) is 1.77 times (95% CI 1.55-2.01) the hazard for monoinfected (n=379,025) or uninfected controls (n=3,111,567). Our analyses indicate that HIV/HCV coinfected individuals are significantly more likely to experience low BMD or bone fracture compared to monoinfected or uninfected controls. The higher fracture rates observed among HIV/HCV coinfected patients might be due to the additive effects of HIV infection and antiretroviral therapy on BMD. Due to the
heterogeneity of the published reports, these conclusions, however, necessitate further study of the association to validate our findings.
The impact of IL28B rs12979860 SNP and advanced liver fibrosis on response-guided therapy in HIV/HCV coinfected patients of particular clinical interest. M. Mandorfer, T. Reiberger, B.A. Payer, et al. ABSTRACT FINAL ID: 943
OBJECTIVE: According to current European AIDS Clinical Society (EACS) guidelines for the treatment of chonic hepatitis C, HCV-Genotype (GT) and rapid virologic response (RVR) exclusively determine chronic hepatitis C therapy duration in HIV/HCV coinfected patients. The aim of our study was to investigate the impact of interleukin 28B rs12979860 SNP (IL28B) and advanced liver fibrosis on the association between treatment duration and sustained virologic response (SVR) in groups of HIV/HCV coinfected patients in which either shortening or extension of treatment duration is recommended. METHODS: 327 HIV/HCV coinfected patients who received antiviral therapy with pegylated interferon plus ribavirin (PEGIFN+RBV) were included in this multinational, retrospective study. Patients with either GT2/3 and RVR (GT2/3-RVR) or GT1/4 without RVR (HCV1/4-noRVR) were divided into groups according to their treatment duration (12-36 vs. 36-60 and 36-60 vs. 60-84 weeks, respectively). Liver biopsies and liver stiffness measurements were available in 289 patients. Advanced liver fibrosis was defined as either METAVIR F3/F4 or liver stiffness >9.5 kPa. RESULTS: Patient characteristics: 81% male, mean age: 40.9±7.6 years, concomitant antiretroviral therapy: 82%, mean baseline CD4+ T-lymphocyte count: 534±251 cells/μl, mean treatment duration: 41.6±16.2 weeks, GT1/4: 68%, advanced liver fibrosis: 42%, IL28B non-C/C: 57%. RVR and SVR were observed in 34% and 53% of patients, respectively. In HCVGT1/4-noRVR patients, a trend toward higher SVR rates (59%) in patients with extended treatment duration (60-84) compared to patients treated for 36-60 weeks (40%) was observed (p=0.055), regardless of IL28B (IL28B C/C: 75% vs. 48%, p=0.117; IL28B non-C/C: 52% vs. 33%, p=0.132). While SVR rates were
comparable between HCV1/4-noRVR patients without advanced liver fibrosis treated for 36-60 and 60-84 weeks (51% vs. 62%, p=0.432), significantly lower SVR rates were observed in patients with advanced liver fibrosis (12% vs. 46%, p=0.022). HCV2/3-RVR patients with shortened treatment duration (12-36 weeks) displayed high rates of SVR ranging from 80% to 100%, regardless of IL28B and advanced liver fibrosis. CONCLUSIONS: Our study supports the extension of therapy duration to 72 weeks for HIV/HCV coinfected patients with GT1/4-noRVR as recommended by current EACS guidelines, regardless of IL28B. Especially GT1/4-noRVR patients with advanced liver fibrosis benefit from 72 weeks of treatment. In patients with GT2/3-RVR, the shortening of treatment duration to 24 weeks is associated with excellent SVR rates, regardless of IL28B and advanced liver fibrosis.
Sustained virological response and occurrence of end stage liver disease event (ESLD) in HIV/HCV-related cirrhosis, ANRS C013 HEPAVIH cohort (France). D. Salmon, P. Sogni, K. Lacombe, et al. ABSTRACT FINAL ID: 952
BACKGROUND: ESLD has become the main cause of severe morbidity and mortality in HIV/HCV coinfected patients. The aim of this study was to assess the impact of anti-HCV treatment on ESLD, (hepatocellular carcinoma (HCC) or liver decompensation ), in HIV/HCV coinfected cirrhotic patients. METHODS: Cirrhotic patients enrolled in the ANRS CO13 HEPAVIH multicenter prospective cohort between 2006 and 2008 with no previous liver decompensation or HCC at cohort inception were included (1). Liver fibrosis stage at
enrolment was evaluated using an algorithm combining liver biopsy and non-invasive liver fibrosis tests previously validated (1). Sustained virological response (SVR) was defined as undetectable serum HCV RNA at 24 weeks after treatment. RESULTS: 241 patients were included and followed-up for a median duration of 3.2 years (IQR: 2.3-4.1). Median age
was 49 years (IQR:46-53), 139 (59%) had a genotype 1, median CD4 was 433/mm3 and 85% had undetectable HIV RNA; 32 patients presented a first liver decompensation or HCC during the follow-up. The cumulative incidence rate of first liver decompensation or HCC, was 4% at one year, 8% at two years, 11.5% at three years, 14% at four years, and 19% at five years.
Overall, 76% (183/241) of patients were treated for HCV (prior to cohort inception or during follow-up) and 24% (58/241) remained treatment naïve. Among HCV-treated patients for whom SVR could be assessed, SVR was present in 33% (51/152) of patients. The proportion of patients with a first ESLD episode was higher among HCV-untreated compared to that in HCV-treated patients (respectively 31% 18/58 vs. 8% 14/183, p<0.001). Among HCV-treated patients, the proportion of patients with a first ESLD episode was higher in patients with no SVR compared to that in patients with SVR (respectively 13% 8/101 vs 2% 1/51, p=0.0035). Indeed, ESLD events in non SVR patients were: 8 liver decompensations (2 hepatic encephalopathies, 4 ascites and 2 ascites with jaundice) and 5 HCC; whereas in patients with SVR, after a median follow-up of 4 years (IQR:2-7) after viral clearance, only one patient was diagnosed with HCC. CONCLUSIONS: SVR in HIV/HCV co-infected patients with cirrhosis is associated with a significantly lower incidence of HCC or liver decompensation. Even if no SVR is achieved, HCV treatment could have a positive impact in this population.
Treatment of acute HCV infection in HIV co-infection: Influence of HCV genotype and ribavirin upon treatment outcome. C. Boesecke, M. Vogel, J.K. Rockstroh, et al ABSTRACT FINAL ID: 49
INTRODUCTION: The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal HCV treatment outcome in HIV co-infected individuals. Here we evaluate the impact of baseline HCV genotype (GT) and added ribavirin (RBV) on sustained virological response (SVR) rates. Material & METHODS: 303 HIV-infected patients from 4 European countries with diagnosed AHC infection were treated
early with pegylated interferon (pegIFN) and ribavirin (RBV) (n=273) or pegylated interferon alone (n=30), followed prospectively and evaluated for virological response rates. Fisher's exact test, chi-square test and binary logistic regression model were used for statistical analysis.
RESULTS: All patients were male, median age was 39 years. Main routes of transmission were MSM (95%) and IVDU (3%). In 75% of patients clinical signs of acute hepatic infection were missing. 69% of patients were infected with HCV GT 1, 4.3% with GT 2, 10.6% with GT 3 and 16.1% with GT 4. Median baseline HCV RNA was 991.500IU/ml, median CD4 T cell count 472 cells/ul. 64,8% of all patients received HAART. By univariate analysis, there were no statistical
differences at baseline for HCV or HIV characteristics between patients with GT 1/4 (group 1) and patients with GT 2/3 (group 2) infection apart from pegIFN + RBV combination therapy: Patients with GT 2/3 were less likely to be treated with combination therapy (p=0,006).
Overall SVR rate was 69.3% (210/303). RVR (p≤0,001), 48w treatment duration (p≤0,001) and GT 2/3 (p=0,024) were significantly associated with SVR. Interestingly, SVR rates were significantly higher in group 2 receiving pegIFN and RBV (33/35) when compared with pegIFN mono-therapy (6/10) (94% vs. 60% respectively; p=0.016). In multivariate analysis, pegIFN/RBV combination therapy (p=0.017) and rapid virological response (RVR) (p=0,022) were significantly associated with SVR in group 2. In group 1, RVR (p≤0,001) and 48w treatment duration (p≤0,001) were significantly associated with SVR. CONCLUSIONS: Treatment of acute HCV GT 2 and 3 infections is associated with higher SVR rates suggesting different cure rates depending on HCV genotype similar to the genotype effects seen in chronic HCV therapy. In addition, ribavirin is important in the management of AHC in HIV-positive patients; for GT 2/3 infections almost all patients clear virus with combination therapy. Early antiviral treatment of acute HCV infection in HIV co-infected individuals results in virological response rates which are significantly higher than those obtained in treatment of chronic HCV co-infection.
Assessment of Boceprevir (VICTRELIS™) Pharmacokinetic/Pharmacodynamic Relation-ships for Sustained Viral Response (SVR) and Occurrence of Anemia : Results in HCV/ HIV Co-infected Patients and in Combined Mono and Co-Infected Patients. L.A. Wenning, R. Liu, K. Tsai, H. et al. ABSTRACT FINAL ID: 770
BACKGROUND: Boceprevir (BOC) is a hepatitis C (HCV) protease inhibitor (PI) approved for treatment of HCV genotype 1 (G1) infection with peg-interferon/ribavirin (PR). In healthy volunteers, BOC concentrations were reduced by ritonavir-boosted HIV PIs. BOC pharmaco-kinetics (PK) in a Phase 2 study in HCV/HIV co-infected patients were characterized, and PK/PD relationships explored with SVR and anemia. METHODS: Co-infection data were from a 48-week trial of 64 subjects on BOC/PR and 34 subjects on PR. A population PK model was used to estimate BOC PK parameters from 281 concentration measurements in 51 patients (94% had an HIV PI in their ARV), taken from weeks 6 to 48 of BOC/PR treatment. PD endpoints were SVR at 12 weeks posttherapy, anemia (hemoglobin <10 g/dL), and severe anemia (Hgb <8.5 g/dL). For some analyses, data were pooled with 209 mono-infected treatment-naïve (SPRINT-2) and experienced (RESPOND-2) patients from Phase 3 studies who had pop PK, SVR24 and anemia data. Logistic regression models assessed the relationship between the event
(SVR or anemia) and BOC PK (AUC, Cmax, or C8hr). The resulting odds ratio (OR) represents the fold-change in odds (probability of event/no event) going from the 25th to 75th percentile of PK values. RESULTS: In the coinfection study, BOC AUC and C8hr were on average 20% and 27% lower compared to Phase 3, but with large overlap in values between co-infected and mono-infected patients. Over the range of BOC PK observed in these studies, no significant relation-ships were observed between any BOC PK parameter and SVR or severe anemia (see table for BOC C8hr; results for AUC and Cmax were similar). Statistically significant relationships were identified between BOC PK and anemia (<10) in the pooled analysis. There was no evident correlation between BOC PK and total RBV dose. CONCLUSIONS: BOC exposure was reduced in the co-infection population compared to mono-infected subjects in Phase 3, most likely reflecting DDI between boosted HIV PIs and BOC. No relationship was observed between BOC PK and SVR, indicating that the reduced BOC exposure is not likely to substantially impact efficacy against HCV. Lower BOC exposure was associated with a reduced incidence of anemia. RBV PK was not collected in the co-infection study, so it cannot be ruled out that this result is confounded by exposure to RBV (which is known to influence rate of anemia).
Clinical factors that predict noncirrhotic portal hypertension (NCPH) in HIV-infected patients: a proposed diagnostic algorithm. N. Parikh, T. Kushner, V. Martel-Laferriere, D. et al. ABSTRACT FINAL ID: 1186
PURPOSE: NCPH is a clinical entity that has been described in HIV-infected patients and is associated with the use of certain antiretrovirals (ARV), especially didanosine (ddI). The purpose of our study was to determine clinical factors that could be used to diagnose NCPH in HIV-infected patients. METHODS: A retrospective case-control study was performed in 42 HIV-infected patients with NCPH and 55 without NCPH. Cirrhosis was excluded with the use of liver biopsy and/or transient elastography. Hepatitis B and C were also excluded. RESULTS:
Cases and controls were similar in age, race, and HIV duration. NCPH patients had a longer mean exposure to ARVs (15.2 vs. 8.2 years, p < 0.001), a lower nadir CD4 count (164 vs. 388 mm3, p < 0.001) and a lower current CD4 count (344 vs. 647 mm3, p < 0.001). More cases than controls were exposed to ddI (92.9% vs 16.4%, p < 0.001). Among the cases, 37 (88.1%) had esophageal varices (EV), 36 (85.7%) had splenomegaly, and 20 (47.6%) had ascites while
only 1 patient (1.8%) had splenomegaly in the control group. The majority (52.4% (n=22)) of cases presented with EV bleeding. Cases also had lower albumin (3.8 vs. 4.5 g/dl, p < 0.001), hemoglobin (12.4 vs. 14.2 g/dl, p < 0.001), platelets (117 vs. 198 x 103/uL p < 0.001) as well as greater alkaline phosphatase (150 vs. 87.2 U/l, p < 0.001), AST (57 vs. 37 U/l, p = 0.002), INR (1.2 vs. 1.0, p = 0.008) and total bilirubin (0.95 vs. 0.58 mg/dl, p = 0.037) compared to
the controls. Mean transient elastography score was higher in the cases (10.6 vs. 5.6 kPa, p < 0.001). Based on this analysis, we hypothesized a set of six criteria to diagnose NCPH in HIV patients (Table 1). Ninety-three percent (n=39) of the cases met at least 3 out of 6 criteria while 96.3% (n=53) of the controls met a maximum of 1 criterion. If meeting 3 of 6 criteria was considered a positive diagnostic test, then the test carried 92.8% sensitivity and 100%
specificity for NCPH. CONCLUSION:This is the largest series of NCPH reported to date. In this cohort, meeting at least 3 out of 6 proposed criteria resulted in a diagnostic sensitivity of 92.8% and specificity of 100% for NCPH in HIV patients. This data suggests a future
larger trial is warranted to further validate these criteria.
Assessment of Boceprevir (VICTRELIS™) Pharmacokinetic/Pharmacodynamic Relationships for Sustained Viral Response (SVR) and Occurrence of Anemia : Results in HCV/HIV Co-infected Patients and in Combined Mono and Co-Infected Patients
L.A. Wenning, R. Liu, K. Tsai, et al. ABSTRACT FINAL ID: 770
BACKGROUND: Boceprevir (BOC) is a hepatitis C (HCV) protease inhibitor (PI) approved for treatment of HCV genotype 1 (G1) infection with peg-interferon/ribavirin (PR). In healthy volunteers, BOC concentrations were reduced by ritonavir-boosted HIV PIs. BOC pharmaco-kinetics (PK) in a Phase 2 study in HCV/HIV co-infected patients were characterized, and PK/PD relationships explored with SVR and anemia. METHODS: Co-infection data were from a 48-week trial of 64 subjects on BOC/PR and 34 subjects on PR. A population PK model was used to estimate BOC PK parameters from 281 concentration measurements in 51 patients (94% had an HIV PI in their ARV), taken from weeks 6 to 48 of BOC/PR treatment. PD endpoints were SVR at 12 weeks posttherapy, anemia (hemoglobin <10 g/dL), and severe anemia (Hgb <8.5 g/dL). For some analyses, data were pooled with 209 mono-infected treatment-naïve (SPRINT-2) and experienced (RESPOND-2) patients from Phase 3 studies who had pop PK, SVR24 and anemia data. Logistic regression models assessed the relationship between the event
(SVR or anemia) and BOC PK (AUC, Cmax, or C8hr). The resulting odds ratio (OR) represents the fold-change in odds (probability of event/no event) going from the 25th to 75th percentile of PK values. RESULTS: In the coinfection study, BOC AUC and C8hr were on average 20% and 27% lower compared to Phase 3, but with large overlap in values between co-infected and mono-infected patients. Over the range of BOC PK observed in these studies, no significant relationships were observed between any BOC PK parameter and SVR or severe anemia
(see table for BOC C8hr; results for AUC and Cmax were similar). Statistically significant relationships were identified between BOC PK and anemia (<10) in the pooled analysis. There was no evident correlation between BOC PK and total RBV dose. CONCLUSIONS: BOC exposure was reduced in the co-infection population compared to mono-infected subjects in Phase 3, most likely reflecting DDI between boosted HIV PIs and BOC. No relationship was observed between BOC PK and SVR, indicating that the reduced BOC exposure is not likely to substantially impact efficacy against HCV. Lower BOC exposure was associated with a reduced incidence of anemia. RBV PK was not collected in the co-infection study, so it cannot be ruled out that this result is confounded by exposure to RBV (which is known to influence rate of anemia).
Prospective Randomized Study Comparing Enhancement of the Antiviral Efficacy between Vitamin D3 (cholecalciferol) and 1α(OH)D3 (alfacalcidol) Administered in Combination with Pegylated-Interferon plus Ribavirin in the Treatment of Chronic Hepatitis C.
N. Nakayama, S. Mochida, J. Funyu, ABSTRACT FINAL ID: 798
BACKGROUND AND AIM: Abu-Mouch et al. reported that SVR ratio increased in patients with chronic hepatitis C when pegylated-interferon (Peg-IFN) plus ribavirin therapy was done in combination with vitamin D intake.In their trial, cholecalciferol, non-activated vitamin D3 supplement, was adopted for the combination therapy, while alfacalcidol, activated 1α-hydroxy (OH) vitamin D3, is generally used for the treatment of osteoporosis. Thus, wedesigned an intention-to-treat prospective randomized study to compare the potentiation of antiviral efficacy between cholecalciferol and alfacalcidol. METHODS: A total of 45 naïve patients with chronic hepatitis C, genotype 1b and serum HCV-RNA levels greater than 5Log IU/mL, were enrolled from 10 hospitals. They were given either of cholecalciferol at a dose of 2,000 IU/day or
alfacalcidol of 0.5 μg/day for 4 weeks, and then they received Peg-IFNα-2a (180 μg/week) plus ribavirin (600 or 800mg/day) in combination with vitamin D similarly as was in lead-in therapy for 48 or 72 weeks according to the response-guided manner. RESULTS: There were 22 and 23 patients, respectively, in the cholecalcidol and alfacalcidol groups. Demographic and
clinical features of patients were similar between both groups. Serum levels of 25(OH)D were increased only in patients in cholecalcidol group during lead-in therapy; the levels at 4 weeks after the therapy were significantly higher than those in alfacalcidol group (p<0.001). In contrast, serum 1α, 25(OH)2D levels were not different between both groups. At present, serum HCV-RNA levels at 12 weeks after the initiation of combined Peg-IFN plus ribavirin therapy
were assessed in 12 patients in each group, and RVR and cEVR were obtained in 4 (33%) and 8 (67%) patients, respectively, in cholecalcidol group and in 1 (8%) and 6 patients (50%) in alfacalcidol group. Among these, 17 patients(71%) showed major allele of IL28B SNPs (rs909917), and the decrease of serum HCV-RNA levels during 4 weeks of the combination therapy was greater in cholecalcidol group (n=9; 5.08 Log IU/mL) than in alfacalcidol group (n=8; 3.99 Log IU/mL) (p<0.05).Conclusion: Non-activated vitamin D3, cholecalcidol, provided superior potentiation of the antiviral activity of Peg-IFN plus ribavirin than activated 1α(OH)D3, alfacalcidol, especially in patients with the major allele of IL28B SNPs. Our clinical obser-vations were in line with the experimental findings obtained using HuH-7 cells (Matsumura T, et al. Hepatology, in press). Impact of cholecalcidol, as compared with that of alfacalcidol, on the antiviral therapy forchronic hepatitis C should be further evaluated through assessment of the SVR ratio.
Extremely low vitamin D levels are associated with increased mortality in patients with liver cirrhosis. F. Grünhage, M. Krawczyk, C. Stokes, M. et al. ABSTRACT FINAL ID: 1561
BACKGROUND: Vitamin D serves an important role in regulating immune response mechanisms, and vitamin D deficiency has been associated with unfavourable outcomes in patients infected with chronic hepatitis C. Patients with advanced liver disease frequently suffer from vitamin D deficiency. However, it remains unknown whether vitamin D deficiency has an
influence on mortality in these patients. Thus, we prospectively studied a cohort of patients with advanced liver disease to assess the influence of vitamin D deficiency on survival. PATIENTS AND METHODS: Ninety-two patients with liver cirrhosis (mean age, 55 years; range, 19-76 years; 66% males; CTP stage C, 41%) were included in our prospective single-center survival study. Serum for determination of vitamin D status was available from 61 patients. AUC analysis, Chi-square statistics and multivariate binary regression analysis were used to
determine the optimal cut-off. Vitamin D levels were determined using a chemiluminescence immunoassay. RESULTS: Median vitamin D levels were 8.2 ng/ml (range <4 ng/ml – 95.8 ng/ml) Overall, 51% of patients (31/61) died during a minimal follow-up of 24 months. AUC analysis determined a vitamin D level of 6 ng/ml as optimal cut-off for discriminating survivors from non-survivors. Kaplan-Meier analysis of survival confirmed low vitamin D levels as a
significant predictor of death (p=0.004). Of note, multivariate analysis identified low vitamin D levels (OR = 6.3; CI: 1.2 – 31.2; p=0.024) and MELD scores (OR = 1.4; CI: 1.2 – 1.7; p<0.001) as independent predictors of survival. Patients with low vitamin D levels died more often
from septic complications (43%) than patients with vitamin D levels > 6 ng/ml (20%).
CONCLUSION: Extremely low serum levels of vitamin D levels are associated with increased mortality in patients with advanced liver disease. Infectious complications are more frequent in these patients. We speculate that a impaired immune function due to vitamin D deficiency may explain this observation. Further studies in larger cohorts are warranted to replicate this finding.
PNI and CONUT as Potential Tools for Nutritional Assessment in Patients with Chronic Liver Disease. E. Taniguchi, T. Kawaguchi, M. Itou, T. et al. ABSTRACT FINAL ID: 1554
BACKGROUNDS & AIMS: A lot of patients with chronic liver disease are at risk of malnutrition. Therefore, simple and useful methods of nutritional assessment are required for ordinary medical care. Prognostic nutritional index (PNI) and controlling nutritional status (CONUT) are simple assessments constructed of only two or three biochemical examinations of blood (albumin, total lymphocyte count, and total cholesterol). We investigated the potential of PNI and CONUT as a nutritional assessment tool in patients with chronic liver disease. PATIENTS & METHODS: We enrolled 165 patients, aged 18–85 years, with chronic liver disease. These patients were nutritionally assessed by PNI or CONUT, demonstrating the association with the severity of chronic liver disease or anthropometric values such as body mass index (BMI), mid-arm muscle circumference (AMC), or triceps skinfold thickness (TSF). Nutritional status was classified into four degrees of severity as follows: PNI≥50 or CONUT 0 or 1, no malnutrition; 40≤PNI<50 or CONUT 2–4, mild malnutrition; 30≤PNI<40 or CONUT 5–8, moderate malnutrition; PNI<30 or CONUT 9–12, severe malnutrition. The severity of chronic liver disease was classified into four degrees as follows: chronic hepatitis (CH) or liver cirrhosis (LC, Child-Pugh class A, B, and C). Nonparametric multiple comparisons among the groups were analyzed by the Kruskal–Wallis test. RESULTS: The value of PNI was significantly decreased according to the severity of chronic liver disease (CH 43.4, LCA 41.9, LC-B 33.6, and LC-C 30.0, P<0.001). Similarly, the value of CONUT was significantly increased (CH 3.3, LC-A 3.7, LC-B 7.6, and LC-C 8.8, P<0.001). On the other hand, BMI, AMC, or TSF showed no significant association with the severity of chronic liver disease. According to the nutritional status assessed by CONUT, the anthropometric values of BMI (none 25.7, mild 23.0, moderate 22.9, and severe 22.3, P<0.05), AMC (none 104.4%, mild 99.5%, moderate 96.0%, and severe 92.7%, P<0.001), and TSF (none 139.7%, mild 110.3% moderate 98.6%, and severe
88.2%, P<0.001) were significantly decreased. Similarly, the values of AMC (none 108.3%, mild 98.6%, moderate 95.7%, and severe 94.1%, P<0.05) and TSF (none 126.1%, mild 115.2%, moderate 99.9%, and severe 88.2%, P<0.05) were significantly decreased according to the nutritional status assessed by PNI. CONCLUSIONS: Because PNI and CONUT were well associated with both the severity of chronic liver disease and anthropometric values, these are potential tools for nutritional assessment in patients with chronic liver disease. In addition, these methods would be useful for ordinary medical care because of their simplicity.
Safety and anti-HCV Effect of Prolonged Intravenous Silibinin in HCV-Genotype 1 Subjects in the Immediate Liver Transplant Period. R. Bárcena, M.A. Rodriguez-Gandía, A. Albillos, et al. ABSTRACT FINAL ID: 210
BACKGROUND: HCV reinfection after liver transplantation (LT) is the rule in patients with HCV-cirrhosis, and HCV-RNA reaches pre-LT levels within the first month after LT. Intravenous Silibinin (iv-SIL) monotherapy has shown a potent in vivo anti-HCV effect, regardless HCV genotype or IL28B genotype. OBJECTIVE AND METHODS: To assess the safety and anti HCV effect of prolonged iv-SIL administration (20mg kg/d) started immediately before LT and maintained thereafter for at least 21 days in 9 consecutive HCV-LT subjects with
HCV genotype 1 since September 2011, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects receiving the same immunosuppressive regimen: Basiliximab (day 0 and 4), Prednisone 20mg/day with progressive tappering, Tacrolimus started at day 3, micophenolate mofetil (1g bid). RESULTS: Both groups showed similar baseline features (age, gender, HCC as the indication for LT, HCV-RNA, bilirubin, AST, ALT, creatinin). All subjects in iv-SIL group showed significant, maintained and progressive decreases in HCV-RNA levels, with no viral breakthrough during therapy (Table 1). Mean HCV-RNA drop at week 3 was -4.1±1.3 log10 IU/ml(-2,41; -6.36). Four patients (44%) reached negative HCV-RNA, maintained during iv-SIL treatment, vs none in the control group, but HCV-RNA relapsed in all after a median of 20,5 days (16-28) following iv-SIL withdrawal. There was a trend to lower baseline HCV-RNA levels in patients with HCV RNA negativization (5.1±0.8 vs
5.7±0.5 log10 IU/ml p=0.1). iv-SIL cases not reaching negative HCV-RNA (iv-SIL-P) showed marked decreases in HCV-RNA when compared to controls (Table 1). Treatment was extended to 6 weeks in two iv-SIL cases reaching HCV-RNA negativization after week 2. There were not clinical adverse effects, and, as reported previously, iv-SIL produced asymptomatic transient hyperbilirubinemia (week 2, 4.2±2.2 vs 2.5±3.6mg/dl; p=0.02). Acute rejection episodes and analytical post-LT values were similar in both groups. CONCLUSIONS: 1. prolonged iv-SIL monotherapy led to significant and progressive decreases in HCV-RNA after LT, with
negativization in 44%, and no HCV-RNA breakthrough during treatment. 2. this potent antiviral effect, however, was not able to avoid HCV recurrence after LT. 3. prolonged iv-SIL was safe, with transient asymptomatic hyperbilirubinemia as the only analytical effect.
Remote rural therapy of Hepatitis C patients by telemedicine can be facilitated by the use of paired wireless Bluetooth electronic stethoscopes. A. Moore, R.A. ABSTRACT FINAL ID: 77
Hepatitis C therapy is particularly challenging in rural communities, where the resources and expertise for safe and effective treatment are generally non-existent. Even when teleconferencing technology is available, the ability to assess and examine patients on treatment is often not adequate to ensure the safety of the treatment. Of particular concern is the risk of cardiac and pulmonary complications, which although uncommon, are potentially severe and life threatening. The provider can normally evaluate patients for these potential complications with a careful exam of the heart and lungs. In this study, Bluetooth® enabled wireless stethoscopes used with a PC-based communication software were deployed at both the site of the provider and the patients, allowing the auscultation of the heart and lungs by the remotely linked provider with exceptional clarity. The study was conducted between the “hub” office of North Country HealthCare, a federally qualified healthcare clinic in Flagstaff, Arizona and rural satellites in the northern Arizona communities of Springerville, Eager, Winslow, Show Low, Holbrook and Kingman. 78 patients were evaluated as potential candidates for Hepatitis C antiviral therapy and
over the subsequent 18 months, 25 patients completed the 6 or 12 month course of therapy with pegylated interferon and ribavirin with telemedicine visits conducted on a monthly basis. The physical examinations were conducted with the aid of the (3M™ Littmann®Electronic Model 3200 Stethoscope, a commercially available digital, cardiology-grade stethoscope with the capacity to record and send real-time sounds to a computer in the exam room via Bluetooth.
The 3M™ Littmann® Scope-to-Scope Tele-Auscultation System software enabled the stethoscope signal to be sent in real time from one stethoscope to another via two computers on the secure network. Support staff in the satellite sites were trained in the presentation of the patients to the hub provider using the video network. Initial physician examination auscultation findings were verified by providers at the satellite sites and were recorded independently.
During therapy, abnormal auscultatory findings were detected and confirmed in 2 patients, resulting in the ordering of chest radiograms to evaluate for pulmonary complications.
CONCLUSION: The utilization of electronic Bluetooth® enabled stethoscopes used with software affords the opportunity to safely evaluate and treat patients with Hepatitis C antiviral therapy in remote locations. Patients who otherwise would not have access to specialty care at this level can benefit by the application of this promising new technology.
The Chronic Liver Disease Questionnaire- Hepatitis C (CLDQ-HCV): A Sensitive and Valid Health Related Quality of Life Instrument. A. Loria, C. Escheik, L. Gerber, et al. ABSTRACT FINAL ID: 937
BACKGROUND: The biopsychosocial model of health has been shown to have utility as a treatment outcome measure for patients with chronic liver disease (CLD). The use of patient reported outcomes (PROs) such as health-related quality of life are important in natural history and efficacy trials. CLDQ-HCV is a disease-specific health related quality of life (HRQL) instrument developed for patients with chronic hepatitis C (CH-C). AIM: To demonstrate
that CLDQ-HCV identifies significant differences in HRQL between patients with CH-C and healthy blood donors (BD), and can detect meaningful change in HRQL over time. METHODS: 162 subjects were included [62 CH-C and 100 BD]. CH-C patients received PEG-Interferon and Ribavirin (PEG-IFN+RBV) with duration based on genotype and virologic response. During treatment, CH-C patients completed CLDQ-HCV questionnaire. Scores are based on a
Likert scale from 0 (worst) to 7 (best), and measure Activity/Energy (AEM), Emotion (EMM), Worry (WOM), Systemic (SYM) and CLDQ-HCV Total score. Clinical data were also collected. Patients completed CLDQ-HCV questionnaires at baseline, 4, 24 weeks of treatment and 24 weeks follow-up. Baseline and follow-up HRQL scores were compared to to baseline scores and to scores from BD. A clinically important difference for CLDQ-HCV scores is defined as
score change of 0.5. Mann-Whitney U test was performed on demographic and questionnaire data. RESULTS: The baseline CLDQ-HCV total score for CH-C patients was 5.7±0.7 vs. 6.2±0.5 for BD (p<.0001). Domain scores for CLDQ-HCV were also significantly lower for CH-C patients [Emotional Domain of CLDQ-HCV (EMM): 5.9±0.4 (BD) vs. 5.6±0.6 (CH-C) (p<.003), Worry Domain (WOM) 6.9±0.2 (BD) vs. 5.7±0.9 (CH-C) (p<.0001)]. During treatment with PEG_INF+RBV, CLDQ-HCV total scores fell rapidly by 4 weeks of treatment (CH-C: 5.4±0.9) and remained low until the end of treatment (5.68±0.8). All scores improved after discontinuation of treatment and CLDQ-HCV total score reached 6.3±0.6 at 24 weeks of follow-up. For patients who achieved sustained virologic response, CLDQ-HCV total
score was 6.6 which is significantly higher than baseline scores for CH-C and higher than healthy blood donors. CONCLUSIONS: The CLDQ-HCV questionnaire is able to distinguish differences between CH-C patients and healthy BD controls. In addition, CLDQ-HCV is sensitive to change over time, and demonstrated meaningful clinical change in HRQL in CH-C patients treated with PIR. This provides additional data for validity of CLDQ-HCV.
Check Hep C: A Demonstration Project for Providing Comprehensive Community-Based Screening, Linkage and Medical Services to New Yorkers with or at Risk for Chronic Hepatitis C Infection. A. Jordan, E.J. Rude, N. Johnson, J. et al. ABSTRACT FINAL ID: 135
BACKGROUND: Hepatitis C virus infection (HCV) disproportionately affects marginalized and stigmatized populations such as drug users, the homeless, and immigrants from high prevalence areas, many of whom lack health insurance and social support and, thus, experience difficulties accessing and maintaining HCV-related care. To help reduce illness and death from HCV, the New York City Department of Health and Mental Hygiene developed the Check Hep C program which includes 1) community awareness, 2) expanded HCV screening and diagnosis, 3) support to link HCV RNA positive patients to services, and 4) mentoring and training of community physicians. METHODS: Using Knowledge Translation as our theoretical framework, Check Hep C was developed to address individual and structural-level barriers to the implementation of these evidence-based HCV screening and care practices. RESULTS: Beginning 5/2012, a diverse set of community partners located in neighborhoods with excess numbers of reported cases of HCV began collaborating on Check Hep C. Screening of high risk individuals is conducted in syringe exchange programs, a drug users' union and federally-qualified health centers (FQHCs). Each participant with a positive HCV RNA test is assigned to a patient navigator, who provides HCV education and counseling, assists with enrollment in benefits programs, accompanies patients to medical appointments, refers patients to supportive services such as housing and substance use treatment, and facilitates effective patient-provider communication. Clinical providers at FQHCs receive in-person and telemedicine mentoring from academic HCV clinicians. A community-wide electronic medical record has been implemented to ensure continuity of care starting from initial contact with Check Hep C program providers; this system will record patient outcomes related to diagnosis, retention in care and response to treatment. DISCUSSION: Although treatment of HCV can be curative and reduce morbidity and mortality, many chronically infected individuals remain undiagnosed and do not receive appropriate care or treatment. Check Hep C seeks to address these gaps at the community level by increasing the capacity to screen, diagnose and care for patients with chronic HCV and to coordinate services within a large urban area where many people are at risk of HCV and many barriers to care exist.
Hepatitis C population in Germany, changing over time. D.M. Klass, H. Hinrichsen, |G. Teuber, et al. ABSTRACT FINAL ID: 958
BACKGROUND AND AIMS: The disease burden of chronic hepatitis C (CHC) is well known. Treatment advances over the last years with individualized regimes and very recently with the introduction of protease inhibitors changed the landscape of hepatitis C treatment. How the hepatitis C patients characteristics shifted over the course of these treatment advances is largely unknown. In order to evaluate the change of the CHC population, we retrospectively analyzed data from three German PegIFN/RBV observational studies. METHODS: Three German-wide, internet-based, non-interventional studies were assessed in cooperation with the Association of German Gastroenterologists in private practice (bng) and Roche (ML17071 and ML19464 from 2002-2007 and ML25724 ongoing from fall 2011). These real-life cohort studies assessed the safety and efficacy of PegIFN 180 μg/w plus weight-based RBV (800–1200 mg/d) for up to 48 weeks and in addition assessed screening parameters for patients that were not treated. Until March 2012, for ML17071/19464 19,115 patients (8563 treated, 10552 not treated) and for ML25724 1,768 patients (1350 treated, 418 not treated) with CHC were included. RESULTS: In general, compared to the two earlier studies (ML17071/ML19464) in the most recent and ongoing study ML25724 the CHC patients are older, have a longer disease duration, show more often signs of an advanced disease and have had prior hepatitis C treatment with a non-response or relapse (Table). Predominant reasons for decision not to start treatment directly in genotype 1 patients are patients refusal because of fear of treatment (ML25724 51%, ML17071/ML19464 26%) and decision to treat at some later time point (ML25724 44%, ML17071/ML19464 14%).
CONCLUSIONS: During the course of at least 5 years, the German populations with chronic hepatitis C progressed in age, disease severity and overall parameters that are associated with poor treatment response. This might be largely accountable to the negative selection of prior hepatitis C treatment attempts.
Hepatitis E virus infection among chronic hepatitis C-infected patients: risk factors and clinical outcome. D. Hotho, B.E. Hansen, H.L. Janssen, R.J. de Knegt. ABSTRACT FINAL ID: 969
BACKGROUND AND AIMS: Acute hepatitis E virus (HEV) infection is emerging in industrialized countries and can cause severe hepatitis in immunocompromised patients. Data on prevalence are scarce and the exact routes of transmission in both immunocompetent and immunocompromised patients need to be determined. Furthermore, it is unclear if HEV-co-infection, like hepatitis A virus infection, could lead to worsening of liver disease in chronic
hepatitis C virus (HCV) infected patients. We studied prevalence of and risk factors for HEV infection among chronic HCV-infected patients. METHODS: For our analysis of risk factors, we used a well defined cohort of chronic HCV-infected patients who were treated with peginterferon/ribavirin between 2000 and 2009. Patients of whom a pretreatment serum sample was available were included. Anti-IgM-HEV and anti-IgG-HEV serum antibody detection was performed using an enzymelinked immunosorbent assay (Wantai, Singapore). RESULTS: 321 chronic HCV-infected patients were treated in the study period and 261 patients could be included. Mean age was 45 years (14-70) and patients were predominantly male (67%), of European origin (72%) and 59 patients (23%) had cirrhosis. Anti-IgG-HEV was positive in 54 patients (21%) and anti-IgM-HEV was positive in 1 patient (2%). Following multivariate regression analysis, older age (OR 1.0, p=0.02), Egyptian origin (OR: 6.3, p=0.02) and the
absence of injecting drug use (IDU) (OR 3.0, p=0.02) were associated with positive IgG-HEV serology. Within European patients, multivariate regression analysis identified age (OR 1.1, p=0.01) but not non-IDU (p=0.06) as risk factor of positive HEV serology. Sixteen (27%) patients with and 38 patients without cirrhosis showed positive IgGHEV serology (p=0.1). Even with correction for age, positive IgG-HEV serology was not associated with the presence
of cirrhosis (p=0.6). CONCLUSIONS: Among HCV-infected patients, HEV prevalence is high (21%) and associated with older age, Egyptian origin and the absence of a history of IDU. Patients affected do not show chronic HEV co-infection or more severe liver disease. These risk factors for positive HEV IgG-serology suggest dietary practices as route for transmission for HEV and contradict the previously reported risk of IDU for HEV infection.
Hepatitis C infection in Italian Psoriatic patients: prevalence and correlation with psoriasis severity score. G. Barbarini, A. Perretti, L. Sangiovanni. ABSTRACT FINAL ID: 973
OBJECTIVES: The incidence of Hepatitis C and psoriasis in the Western World is respectively 2.6% and 0.8 to 3%. A link between these two conditions has been recently focused. We evaluated the prevalence of Hepatitis C in patients with psoriasis and its correlation with psoriasis severity. METHODS: 184 psoriatic patients were included in our study ; we considered their liver function data , virological parameters (HCVAb , HCVRNA and genotypes) and PASI (Psoriasis Area and Severity Index). 2154 healthy subjects from the general population represented our control group. RESULTS: We found a higher prevalence of Hepatitis C markers in psoriatic patients than in healthy subjects (7.7% vs 3.3% p=0,005) ; this prevalence increased with age in both groups. Psoriatic patients HCVAb positive ,either RNA+, either RNA-, showed a mean PASI score significantly increased compared to HCVAb negative ones (11,5±10.2 p<
0,001). In HCVRNA positive patients we observed onset or worsening of psoriasis during Interferon pus Ribavirin treatment even if their main PASI score was not different from that of HCVAb+ RNA+ or RNA- psoriatic patients not receiving IFN therapy (27.6±16.4 vs20.6±11.6 respectively). CONCLUSIONS: This study shows an association between Hepatitis C and Psoriasis and emphasizes the role of HCV screening in all psoriatic patients in order to decide the optimal treatment strategy for both infections. An important role of HCV infection in the pathogenesis of this skin disease could be supposed ; in HCV+ patients PASI is more severe than in HCV- ones. Interferon treatment for HCV infection can trigger the onset of psoriasis or worsen its symptoms.
Characteristics and Clinical Management of a Large Cohort of Hepatitis C Patients from a Northern California Integrated Health Plan. M. Manos, V. Shvachko, M. Pauly, et al. ABSTRACT FINAL ID: 965
BACKGROUND: The population health perspective on hepatitis C is evolving rapidly as direct-acting antiviral therapies are introduced and birth cohort based HCV screening recommendations are implemented. We evaluated the characteristics and management of a hepatitis C cohort just prior to these changes. METHODS: We studied adult chronic hepatitis C patients in the Northern California Kaiser Permanente Medical Care Program with
health plan membership for ≥15 months July 2009 - December 2010. Patients with HIV (2%), chronic HBV (2%) and history of end stage liver disease, hepatoma, or liver transplant (6%) were excluded. Data were obtained from electronic records. Care measures were assessed for July 2009-December 2010 (study window), or as “ever” based on records for 1995-2010. RESULTS: Findings for the 10,809 eligible patients are below. Most (79%) were baby
boomers born 1945-64, 27% had history of drug abuse. Over 70% were in the health plan for >10 years. Of the 74% with HCV genotype (GT) results, 69% were GT1. Before the study period, 12% had evidence of sustained virologic response to therapy. During the period, 73% had a visit for hepatitis care and 5% received treatment. Patients with specialist (20%) versus primary care (53%) visit(s) for hepatitis were more likely to receive a comprehensive panel of
liver tests (61% vs. 25%, p<.0001). CONCLUSIONS: In this community-based hepatitis C cohort, almost a third had received HCV treatment, and almost half had a liver biopsy. Many were using psychotropic and/or opioid prescription drugs. Screening for HAV and HBV was common; comprehensive liver testing was less frequent. Patients evaluated by a specialist were most likely to receive liver-specific management. The findings reveal common comorbidities, as well as opportunities for improved care. Future studies will determine how new antivirals impact patterns of care, and whether broader screening will substantially alter the demographic and clinical composition of hepatitis C patient populations.
Prioritization of Hepatitis C Patients For Treatment with Direct Acting Antiviral Agents
J. Chhatwal, M.S. Roberts, |M.A. Dunn, M.S. Roberts, K.B. Chopra. ABSTRACT FINAL ID: 152
PURPOSE: The launch of direct-acting antiviral agents (DAAs) saw a surge of patients requesting treatment for chronic hepatitis C who had deferred treatment with peginterferon-ribavirin, which resulted in waiting lists of patients because of a limit on the number of patients who could initiate treatment every week. Such waiting lists are also expected where DAAs will become available in the future or when next-generation DAAs become available. Our purpose was to formulate need-based prioritization of patients for treatment with DAAs that would maximize their value to society. METHODS: We developed a decision-analytic Markov model that simulated the treatment regimens of the FDAapproved DAAs and the natural history of hepatitis C disease. Our model’s states included METAVIR fibrosis score (F0–F4), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), liver-transplant (LT), and liver-related deaths (LRD). We used efficacy data from the registration trials of telaprevir and boceprevir—ADVANCE, REALIZE, SPRINT-2 and RESPOND-2, and estimated progression rates of hepatitis C disease from previously published studies. We compared two scenarios: (1) get immediate treatment; (2) get treatment after 1-year because of resource scarcity; and projected quality-adjusted life-years (QALYs), incidence of DC, HCC, LT and LRD per 1000 patients. We evaluated the impact of wait for treatment by fibrosis stage, previous treatment response (relapse, partial-response and null-response), IL28B polymorphism, age, and sex. RESULTS: The projected gain in QALYs by immediate treatment versus receiving treatment after 1-year in a 50-year old cirrhotic patient who is treatment naïve, prior relapser, partial responder and null responder were 0.54, 0.71, 0.51 and 0.27, respectively. The corresponding reductions in the incidence of DC, HCC, LT and LRD per 1000 patients were between 10–24, 12–31, 2–5 and 17–44, respectively. The gains in QALYs by immediate treatment in cirrhotic patients by IL28B genotype were between 0.52–0.76 (highest in C/C genotype). The gain in QALYs in F0–F3 patients by immediate treatment was between 0.04–0.07. In addition, the gain in QALYs in younger patients was higher than that in older patients. CONCLUSIONS: Our recommended prioritization order (from highest to lowest) by patient characteristics is: (1) Cirrhosis ([a] younger age, [b] prior relapser, [c] treatment naïve, [d] IL28B genotype C/C, [e] partial responder [f] others), (2) METAVIR score F3 ([a] younger age, [b] others), and (3) METAVIR score F0–F2. We provide a need-based prioritization of patients that is clinically intuitive and will maximize the value of DAAs to society.
Indications for Screening among Reported Cases of Hepatitis C Virus Infection from Enhanced Hepatitis Surveillance Sites—United States, 2004–2010. R. Mahajan, S.J. Liu, M. Klevens, et al. ABSTRACT FINAL ID: 944
OBJECTIVES: Risk-based screening for hepatitis C virus (HCV) infection has been considered
unsuccessful in identifying many HCV-infected US residents. Thus, the Centers for Disease Control and Prevention (CDC) is developing recommendations to screen persons born from 1945 through 1965, the ‘Baby Boom’ cohort, many of whom are unaware of their infection. Using 2004-2010 data from four enhanced surveillance sites, we examined indications for screening by birth cohort (before 1945, 1945-1965, and after 1965) among reported HCV cases. METHODS: Cases were determined by positive HCV laboratory markers reported to health departments. Upon receiving a new report, the health department conducted a medical chart review of the case to abstract information about demographics and indications for testing. Information was abstracted using standardized case report forms designed by CDC. These forms were collected by health departments to create a surveillance database. RESULTS: Of 110,223 cases of chronic HCV infections reported during 2004-2010, 74,578 (68%) were in persons born during 1945-1965. Indications for screening were abstracted for 45,034 (41%) cases; of these, 29,544 (66%) reported at least one CDC-recommended risk factor as reason for HCV screening. Injection drug use was the main risk factor reported for persons born in birth cohorts after 1945 (60% and 80%). For other non-CDC-specified reasons for testing—i.e., factors known to be associated with increased risk of infection but not specifically recommended by CDC as reasons for screening-- 40% (17,887/45,034) had a history of incarceration. Overall, about 78% of all chronic HCV cases reported to CDC were in the birth cohort from 1945 through 1965 or had either a history of injection drug use or of incarceration. CONCLUSIONS: These data support proposed new CDC recommended age-based guidelines for screening of HCV in the 1945-1965 birth cohort, especially if supplemented by continued risk-based screening.
Knowledge about Infection is the Only Predictor of Treatment in Patients with Chronic Hepatitis C (CH-C). Z.M. Younossi, M. Stepanova, M. Afendy, et al. ABSTRACT FINAL ID: 961
BACKGROUND: HCV is the leading cause of cirrhosis and liver cancer in the U.S. To potentially reduce the future burden of HCV in the U.S., the Centers for Disease Control (CDC) has recently recommended “Birth Cohort Screening” of the U.S. adult population. Furthermore, HCV treatment regimens with the new Direct Acting Antivirals (DDAs) have better efficacy with shorter duration of treatment. Our aim was to assess independent predictors of receiving treatment in a cohort of HCV infected patients. METHODS: The Hepatitis C follow-up questionnaires of the National Health and Nutrition Examination Surveys (NHANES) conducted between 2001-2010 were used. The NHANES participants who tested positive for HCV RNA were followed by CDC 6 months after initial testing with questions related to their awareness of their infection and history or intention to receive treatment. RESULTS: A total of
500 NHANES participants were tested positive for HCV RNA and attempted to follow-up. Of these, only 203 had completed the follow-up questionnaire (response rate of 40.6%). Of those, only 101 (50%) knew about their prior knowledge. Furthermore, only 34 HCV-RNA+ patients (17%) had received treatment while 169 (83%) were not treated. Possible reasons for not receiving treatment were not seeing a health professional (26.0%%) or lack of recommendation for follow-up (31.4%), fear of unpleasant side effects (5.9%), unwillingness to do self injections
(3.0%), high cost of treatment (7.7%) and hope for a better treatment (2.4%). In multivariate analysis, prior knowledge about their HCV infection in HCV-positive individuals was independently associated with receiving routine care from a doctor or HMO [OR (95% CI)=2.481 (1.087-5.662)] as was higher income (relative to poverty threshold for that year)
[OR=1.447 (1.077-1.944)]. Furthermore, being male [OR=0.302 (0.126-0.725), being in good to excellent health [OR=0.368 (0.149-0.912)], and consuming excessive amounts of alcohol [OR= 0.207 (0.068-0.636)] were all independently associated with the lack of awareness about being infected with HCV. On the other hand, although a number of variables (such as health insurance, education, co-morbidities) demonstrated trends for association with having received treatment, “prior knowledge” about their HCV infection was the only independent predictor of receiving anti-HCV treatment [OR: 4.364 (1.618-11.77)]. CONCLUSIONS: Knowledge about having HCV infection is the only independent predictor of receiving treatment. Therefore, Birth Cohort Screening of the U.S. general population could lead to wider identification of HCV and potentially better management of the future burden of HCV and its complications.
Acoustic Radiation Force Impulse Imaging for evaluation of antiviral treatment response in chronic hepatitis C. M. Friedrich-Rust, N. Forestier, A. Gaus, C. Sarrazin, L. Gerber, M. Schneider, G. Dultz, S. Zeuzem, ABSTRACT FINAL ID: 1375
PURPOSE: Antiviral therapy can stop progression of liver fibrosis and partially reverse it. Non-invasive methods have not only shown good diagnostic accuracies for the assessment of liver fibrosis, but have also shown similar results to liver biopsy for the prediction of long-term survival. First studies have shown that transient elastography (TE) can be used to monitor fibrosis after antiviral therapy. Acoustic Radiation Force Impulse (ARFI)- Imaging is a novel ultrasound-based elastography method which is integrated in a conventional ultrasound machine
enabling the combination of elastography and conventional screening ultrasound. The aim of the present study was to demonstrate a significant difference of ARFI –values in patients with sustained virological response (SVR) and in patients without SVR (Non-response/Relapse).
Materials and METHODS: 98 patients infected with chronic hepatitis C (mainly with HCVgenotype 1) who received a pegylated interferon and ribavirin-based regimen and had completed antiviral treatment at least 6 months ago (47 patients with SVR, 51patients with non-response/relapse) were prospectively included in the study. All patients received ARFI-imaging, transient elastography and laboratory evaluation on the same day. RESULTS: Significantly lower ARFI and TE values were observed for 47 patients with SVR as compared to 51 patients
without SVR with median ARFI-values of 1.37m/s vs. 2.00 (p=0.0021), and median TE-values 4.9 kPa vs. 11.1 kPa (p<0.001), respectively. CONCLUSION: ARFI-imaging und TE might be useful non-invasive tools to assess liver fibrosis changes in patients with hepatitis C after antiviral therapy. Bar diagram of median ARFI values in the overall patient groups and in the subgroup of patients with SVR and patients with Non-Response/Relapse. The difference between the two subgroups was statistically significant (p=0.0021).
Medication Use in Patients with Chronic Hepatitis C (HCV) from a U.S. Commercial Claims Database: Inadequacy of Prescribing Information for Assessment of Potential Drug Interactions. C.L. Mayer, J.C. Lauffenburger, J.F. Farley, et al. ABSTRACT FINAL ID: 136
PURPOSE: It is important that practitioners are adequately prepared to assess CYP3A and P-gp drugdrug interaction (DDI) potential when initiating triple therapy in patients with HCV. To determine how frequently practitioners are required to assess DDI potential, the 20 most frequently filled prescriptions and the most widely used drugs with suspected DDI potential were identified. Prescribing information was evaluated. METHODS: Chronic HCV patients (ICD-9 070.54, 070.44) ≥ age 18 were identified in a large claims database. Continuously enrolled patients with ≥1 inpatient or ≥2 outpatient diagnoses were grouped into yearly cross-sectional cohorts from 2006-2010. Medications were ordered by number of claims. Drugs with the potential to interact with boceprevir (BOC) or telaprevir (TVR) were identified from www.hep-druginteractions.org. One claim per cross-section was required to identify patients with pharmacy benefit using drugs with DDI potential; drugs with ≥5% use were assessed. Patients
could contribute to multiple cross-sections if meeting criteria for multiple years. RESULTS: Of 121,163 patients ≥18 with chronic HCV, 71,584 met the study criteria and 53,461 (79,185 cross-sections) had a pharmacy benefit. Mean age was 51.2 ± 7.5 years; 62.2% were male. Of the 20 most frequently filled prescriptions, 6 have DDI potential; 4 have clear recommendations for management. Twenty drugs with DDI potential and ≥5% use were identified. Of these,
approximately 5% are contraindicated with either BOC or TVR; 5% and 15% have recom-mendations to avoid use for BOC and TVR; 25% and 35% have recommendations to reduce the dose and/or monitor for BOC and TVR; and 65% and 45% lack a recommendation in the prescribing information for BOC and TVR, respectively. CONCLUSION: Drugs with the potential to interact with BOC and TVR are frequently utilized by patients with HCV. Current prescribing information does not adequately prepare practitioners to assess DDI potential for approximately half of the drugs they are likely to encounter. These data can inform more targeted DDI recommendations.
Percent of population using drugs with DDI potential
zolpidem 17.4* diazepam 7.9
codeine 16.0 bupropion 7.2*
prednisone 15.4 trazodone 7.1
tramadol 14.3* fluconazole 6.8
citalopram 13.5 sertraline 6.4
fluticasone 13.1 clarithromycin 6.1
methylprednisolone 13.0 sildenafil (Viagra) 5.4
alprazolam 11.8* clonazepam 5.3
amlodipine 10.2* simvastatin 5.2
escitalopram 8.1* venlafaxine 5.0
*one of the 20 most frequently filled
Screening for hepatitis C viral Infection in a tertiary care cancer center. A. Saxena, P. Mahale, D.P. Kontoyiannis, H.A. ABSTRACT FINAL ID: 970
BACKGROUND: Screening for hepatitis C virus (HCV) in persons with risk factors can lead to early identification of infected patients. As a result, risk-based screening is currently recommended by the AASLD/IDSA/ACG guidelines. There is paucity of information regarding HCV screening in cancer patients, a group with significant morbidity and mortality. Therefore we sought to determine the effectiveness of risk factor-guided and birth cohort screenings for early recognition of HCV infection in a tertiary care cancer center. METHODS: Patients with hematological malignancies (leukemia, lymphoma, stem cell transplantation) are routinely
screened for anti-HCV antibody (HCVab) at the initial visit to our center. The study group included all patients with hematological malignancies who tested positive for HCVab between January 2008 and December 2011. Patients with a known history of HCV infection prior to screening were excluded. Risk factors were defined per AASLD/IDSA/ACG guidelines and their identification accuracy was determined among primary oncologists based on data collected from
medical records. Following the new CDC recommendation, the number of patients with positive HCVab born from 1945 through 1965 (“baby boomers”) were identified. RESULTS: Two hundred and fifty-nine patients with hematological malignancies tested positive for HCVab on routine screening during the study period. The exclusion of those with a history of HCV left a subgroup of forty-nine patients who were further analyzed. Only 10 (20%) of 49 patients were identified with at least one risk factor by the primary oncologists. Most patients [33/49 (67%)] with new HCVab were born from 1945 through 1965. The majority [37/49 (76%)] of patients analyzed either fell inside the birth cohort or had an identifiable risk factors for HCV. CONCLUSION: A targeted risk-based screening program for recognition of HCV might be suboptimal in cancer centers. Relying on a patient’s history alone may not be adequate enough to identify patients with serological evidence of HCV. However, future implementation of a policy that integrates assessment of HCV risk factors and birth cohorts screening likely will improve the detection rate of HCV.
Molecular and Epidemiological Profiles of Hepatitis C Virus in Mainland China. W. Ju, S. Yang, Q. Wang, H. et al. ABSTRACT FINAL ID: 941
Determination of HCV genotype is significant for the prediction of response to anti-viral therapy and duration of treatment. This is an epidemiological study of patients infected chronically with HCV in mainland China. A total of 853 HCV RNA positive serum samples were collected from chronic HCV infected patients from 23 administrative units in mainland China during 2009.10 - 2011.6. The serum samples were subjected to RT-PCR followed by direct DNA sequencing and phylogenetic analysis of NS5B and/or CORE-E1 regions. HCV genotypes were available in 811 samples [95.1% (811/853)]. The results indicated new trends of HCV infection in mainland
China. Phylogenetic analysis revealed that genotype 1, 2, 3 and 6 were detected. No genotype 4 and 5 strains were found. The distribution of HCV subtypes was 1b, 2a, 3a, 6a, 3b, 6n, and 1a at frequencies of 73.1%, 18.5%, 3.2%, 2.5%, 1.8%, 0.5%, and 0.4%, respectively. HCV subtype 1b was the most frequent in mainland China followed by 2a. The HCV genotype distribution differed according to the patients’ region of origin and genotypes 3 and 6 represented an increasingly wide range of geographic distribution. Patients infected with HCV subtype 1b and 2a were found statistically older than those infected with 3a, 3b, 6a and 6n, respectively. Blood transfusion was the main route of transmission. IDUs and tattooing / piercing were more common among patients with genotype 3 compared with those with genotype 1. This study is the largest report of molecular epidemiology of HCV in mainland China and demonstrates a genetic heterogeneity of HCV infection, with at least four HCV genotypes and seven subtypes. Clinical
trials of direct anti-HCV agents (DAA) should consider this genetic heterogeneity.
Screening for HCV based on traditional risk factors in foreign-born communities in NYC misses many infected persons. P. Perumalswami, S.H. Factor, L. Kapelusznik, et al. ABSTRACT FINAL ID: 938
An Institute of Medicine Report in 2010 focused on the unmet need to identify persons with chronic viral hepatitis. At least 10% of persons with chronic HCV do not fall within the current high-risk groups with traditional risk factors (TRF) for screening. The NHANES III data suggests that HCV prevalence is highest in US residents born from 1945 to 1964 and is likely to be added to current TRF screening guidelines by the Centers for Disease Control (CDC). METHODS: In May 2009 we started Hepatitis Outreach NEtwork (HONE), a viral hepatitis screening and linkage to care program targeting foreign-born communities at risk for HBV & HCV. HONE coordinated efforts with community organizations and the NYC Dept of Health to offer hepatitis teaching sessions and screening. All participants provided consent and testing included HCV Ab. All HCV+ participants were invited for a free follow-up visit. Patient navigators linked participants to care. RESULTS: HONE conducted 25 didactic and screening events from May 2009 to July 2011. Of 1,647 persons screened, 1,603 (97%) consented. The median age was 51, 54% were women, and participants were born in 68 countries. Compared to US population estimates, the study sample had a lower percentage of high school graduates (54% vs. 87%), lower median household income (<$15K vs. $49K) and lower percentage of health
insurance (44% vs. 83%). In univariate analysis of TRF for HCV, injection drug use, HIV, and prior blood transfusion were significantly associated (p < .05). If we had screened for HCV in persons with TRF rather than all patients, only 25 (33%) of the 75 HCV+ persons would have learned of their infection. If we had screened for HCV in persons with TRF and/or persons who were born from 1945 to 1964, only 49 (64%) of the 75 HCV+ persons would have been
diagnosed. If we had screened for HCV in persons with TRF and/or persons who were born from 1945 to 1964 and/or persons born in countries with prevalence of HCV >3%, 61 (82%) of the 75 HCV+ persons would have been diagnosed. Thirty-two (42%) HCV+ attended a follow up visit. Given the anticipated approval of direct acting antivirals, 3 were recommended to start treatment and 2 have started. CONCLUSION: This study supports the addition of CDC’s proposed birth cohort screening to TRF screening for HCV. Screening for HCV in foreign-born communities is
currently not practiced. HONE data supports the IOM’s recommendation to consider screening persons born in Egypt and supports targeted screening in persons born in countries with high HCV prevalence. The study also underscores the persistent challenges in ensuring follow up in patients who need further evaluation and treatment.
Mortality in Status 7 Patients: The Dark Side of the Liver Waiting List? Y. Lee, A.M. Allen, W. Kim, et al. ABSTRACT FINAL ID: 41
BACKGROUND/AIMS: Waitlist mortality is one of the most widely publicized parameters for effectiveness of organ allocation and distribution policies. Under the current liver transplant (LTx) policy, when patients are considered temporarily unsuitable for LTx, they are designated as inactive (‘status 7’). While a large number of individuals belong in status 7 at any give time, the impact of their status on waitlist mortality is not well known. METHODS: All adult primary LTx candidates with end stage liver disease registered on waiting list from January 2005 to
December 2008 were identified in the Organ Procurement and Transplantation Network (OPTN) data. Patients with a diagnosis of hepatic malignancies were excluded. Patients were followed forward in time tracking status changes as well as waitlist deaths. RESULTS: Out of a total of 14,178 waitlist registrants that met the eligibility criteria, 4,095 (29%) were made status 7 at
least once while waiting. We divided the status 7 registrants into two groups: those made inactive with MELD ≦25 and those with MELD >25. The latter is thought to be enriched with patients too sick to transplant, whereas the former is unlikely to include a large number of those patients. In the table, the majority of status 7 patients had low MELD. There was no striking difference in the distribution of diagnosis. As expected, the prevalence of ascites and hepatic encephalopathy was higher in the high MELD group. While survival at 1 year was significantly higher in the low MELD group, more deaths occurred in the low MELD group than the high MELD group. Out of the total 4,313 waitlist deaths, 40% (n=1,729) occurred in the status 7 group, of which majority was in the low MELD group (n=1,218). CONCLUSION: Many LTx recipients become status 7 after waitlist registration. A large proportion of waitlist deaths occur in status 7, a majority with a low MELD. While all death on waitlist represents a tragedy, mortality statistics may need
to be adjusted to exclude patients who are made inactive without real intention for reactivation.
Pain, Narcotic Use, and Healthcare Utilization in Chronic Liver Disease. S. Rogal, ABSTRACT FINAL ID: 138
PURPOSE: Recent attention has been focused on risk factors for high healthcare utilization among patients with cirrhosis, but pain, narcotic use, and psychiatric symptoms have not been evaluated in these models. METHODS: A consecutive sample of 1286 patients with chronic liver disease being seen in an outpatient hepatology clinic was assessed by retrospective chart review. Number of clinic visits, phone calls, and hospitalizations over a 6-month period were collected. Pain was assessed by numeric pain scale. The association of pain and narcotic use with
number of patient phone calls to clinicians or clinic visits was assessed first with t-tests and then with linear regression using stepwise backwards elimination. Chi-square testing and logistic regression models using stepwise backwards elimination were used to determine associations of pain and narcotic use with hospital admission. Models evaluated demographics, history of substance abuse, psychiatric symptoms, and stage, symptoms, and etiology of liver disease
as potential confounders. RESULTS: Over a 6-month period, hospitalization was more common among patients with pain (13% vs. 7%, p<0.0001) and narcotic use (18% vs. 6% p<0.0001). Pain and narcotic use were independently and significantly associated with median number of clinic visits and phone calls (p<0.0001). In multivariate modeling, hospitalization was significantly
associated with narcotic use (OR=2.80, p<0.0001), older age (OR=1.02, p=0.02), Child’s C cirrhosis (OR=4.14, p<0.0001), emotional dysfunction (OR=1.00, p<0.002), and ascites (OR=2.98, p=0.004). In multivariate modeling, subjective complaints of body pain and narcotic use were significantly associated with number of phone calls and clinic visits, as were hepatitis C, nicotine history, advanced cirrhosis, and functional impairment related to emotional
distress. Other factors associated with number of clinic visits included unmarried marital status and non-white race, while number of phone calls was significantly associated with ascites and female gender. CONCLUSIONS: Psychiatric symptoms and the presence of pain were significantly linked to healthcare utilization among patients with cirrhosis and suggest that psychiatric care and pain management should be part of comprehensive medical treatment. Given the association of narcotic use with subsequent hospitalization and healthcare utilization
while controlling for these other factors, a narcotic-sparing pain management regimen may be optimal in chronic liver disease.
Optimal noninvasive markers for fibrosis stage in chronic hepatitis C. M. Lu, L. Lamerato, S.C. Gordon et al. ABSTRACT FINAL ID: 1015
PURPOSE: Several non-invasive, serum-based biomarkers of fibrosis have been developed and
validated for chronic hepatitis C (CHC) under controlled conditions within relatively small, treatment naïve CHC cohorts. Our analysis sought to validate three of those markers, APRI, FIB-4, and AST/ALT ratio, in a cohort of both treated and untreated CHC patients from four HMO Research Network health systems enrolled in the Chronic Hepatitis B & C Cohort Study (CHeCS), utilizing biopsy and laboratory data collected during routine care. METHODS: Liver biopsy results and lab values for aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were abstracted from electronic medical records. Fibrosis scores from different scoring systems (IASL, Batts Ludwig, Metavir, Ishak, Knodell, Scheuer) were mapped to an F0-4 equivalent scale. Among biopsied patients, APRI (AST-to-platelet ratio-index), FIB-4 (based on age, ALT, AST, and platelet count), and AST/ALT ratio were imputed based on lab results collected within 7 days of each other and within 6 months of the biopsy. Logarithmic transformation was applied to normalize the APRI, FIB-4, and AST/ALT ratio distributions. For each of the three markers, analysis of variance (ANOVA) was conducted to detect significance of overall effect, followed by pairwise comparisons between fibrosis levels if an overall effect was detected at p<0.05. The predictive ability of each marker to differentiate advanced fibrosis (F3-F4) from absent-to-moderate fibrosis (F0-F2) was measured by the area under the receiver operating characteristics curve (AUC). Nonparametric Mann-Whitney U test was used test for
significant differences between AUCs. RESULTS: We identified 2202 patients with available biopsy and lab values for imputing APRI, FIB-4, and AST/ALT ratio. Median age at biopsy was 50 years and the fibrosis stage distributions were: 11%(F0), 22%(F1), 28%(F2), 18%(F3) and 21%(F4). For each biomarker, the mean was significantly higher for each successive fibrosis level from F0 to F4 (p<0.05), with the exception of the difference between the F3 and F4 levels for AST/ALT ratio (p=0.11). The AUCs and their 95%CIs in distinguishing severe fibrosis (F3-F4) from absent-to-moderate fibrosis (F0-F2) were: 0.78 (0.76,0.80) for APRI, 0.82 (0.80,0.84) for FIB-4, and 0.64 (0.62,0.67) for AST/ALT ratio. There was a significant difference between the AUCs of FIB-4 and APRI, and between APRI and AST/ALT ratio. CONCLUSION: In a large observational cohort study of both treated and untreated CHC patients, FIB-4 was superior to APRI or AST/ALT ratio at distinguishing severe fibrosis from absent-to-moderate fibrosis.
Diagnostic Performance of a Rapid Magnetic Resonance Imaging Method of Measuring Hepatic Steatosis. M.J. House, T.G. St. Pierre, E.K. Gan, et al. ABSTRACT FINAL ID: 1482
BACKGROUND AND AIMS: Hepatic steatosis is associated with an increased risk of developing serious liver disease and other clinical sequelae of the metabolic syndrome. However, visual estimates of steatosis on histological sections are subjective and reliant on an invasive procedure with associated risks. The aim of this study was to test the ability of a rapid magnetic
resonance imaging (MRI) method to diagnose clinically relevant grades of hepatic steatosis in a cohort of patients with a variety of liver diseases. METHODS: Sixty-two patients with a range of liver diseases underwent liver biopsy and MRI. There were 19 cases with NASH, 17 with hepatitis B or C, 9 with NAFLD, 4 with autoimmune hepatitis, 4 with primary schlerosing cholangitis, and 3 with alcoholic liver disease. Hepatic steatosis was quantified firstly using an opposed-phase, in-phase gradient echo, single breath-hold MRI methodology and secondly, using liver biopsy with visual estimation by a histopathologist and by computer-assisted morphometric image analysis. The area under the receiver operating characteristic (ROC) curve
was used to assess the diagnostic performance of the MRI method against the biopsy observations. RESULTS: Our MRI approach had high sensitivity and specificity at all hepatic steatosis thresholds (Table 1). Areas under ROC curves were 0.963, 0.993, and 0.975 at the NASH CRN thresholds of 5%, 33%, and 66% liver fat, respectively. MRI measurements were strongly associated with visual (r2 = 0.84) and computer-assisted morphometric (r2 = 0.84)
estimates of hepatic steatosis from histological specimens. CONCLUSION: The proposed MRI approach, using a conventional, rapid, gradient echo method, has high sensitivity and specificity
for diagnosing liver fat at all grades of steatosis, irrespective of the underlying liver disease.
Implementation of the First Department of Veterans Affairs Specialty Care Access Network - Extension of Community Healthcare Outcomes (SCAN-ECHO) Program for Chronic Liver Disease G.L. Su, H. McCurdy, A.W. Tai, K.R. et al. ABSTRACT FINAL ID: 134
BACKGROUND: Chronic liver disease continues to be a major problem, with the number of veterans carrying the diagnosis of HCV cirrhosis doubling over the last decade. Primary care providers have limited access to specialists in liver disease, yet are faced with the burden of care for these complicated patients. With the goal of improving access to specialty care, particularly from rural and underserved areas, the VA Ann Arbor Healthcare System, as part of the national Specialty Care Transformation Initiatives, implemented the first SCAN-ECHO program
in chronic liver disease. We modified the method used by Project ECHO, merging case-based distance learning with co-management of care for delivery within the VA health system.
METHODS: Using the electronic consult system, we re-routed cases submitted to the general Liver clinic to Liver SCAN-ECHO clinics after obtaining permission from primary care providers. The Liver SCAN-ECHO clinic occurred via dedicated video-teleconferencing with multiple site participation and consisted of both case-based learning, in which primary care providers interacted with the specialists and received immediate consultation for the patients, as
well as a short didactic session on a liver specific topic. The entire clinic was eligible for continuing medical education credit. Data from these clinics were prospectively collected.
RESULTS: From the period of June 2011 to May 2012, 36 clinics were held. 153 patients were “seen” in this manner with 136 "new" patients and 17 "return" patients. 43 primary care providers participated from 16 sites. These included 4 VA medical centers and their community based outpatient clinics (CBOC). The most common diagnoses were chronic hepatitis C infection, nonalcoholic fatty liver disease, and cirrhosis. The average patient would have traveled
187 miles round-trip (range 14 - 484 miles) to Liver clinic. As a result of the SCAN-ECHO clinic, 28,597 miles of patient travel were saved. Post session evaluations by primary care providers rated the conference. On a scale of 1 to 4 where 1 was “not at all” and 4 was “very much”, primary care providers rated the question of whether the conference addressed “how to implement ideas” at a mean of 3.93 and whether the conference was “relevant to my practice” at a mean of 3.93 (n= 83 evaluations).CONCLUSION: In summary, we demonstrated the feasibility of implementing this innovative model of care for patients with chronic liver disease within the VA health system. In our preliminary assessment, this appears to be a highly
effective method to decrease veteran travel and increase provider competency.
What Factors Explain Excess Risk of Death among Black Liver Transplant Recipients?
N. Lauder, L. Boulware. ABSTRACT FINAL ID: 179
BACKGROUND: Factors explaining well-documented disparities in graft failure among Black liver transplant recipients compared to recipients of other ethnicities have been poorly explored.
METHODS: We examined differences in graft failure among black and white and other ethnic deceased donor liver transplant recipients in UNOS during the post-Model of End Stage Liver Disease (MELD) era (Jan2003-Jan2009). We explored the factors contributing to blacks’ excess hazard of graft failure in time-to-event models, sequentially adjusting for demographic (age, gender), insurance status, and transplant-related factors recipient diagnosis, MELD score, HLA mismatch number. We also explored the role of donor age, gender and ethnicity as potential risk factors. RESULTS: Among 12,727 total recipients, blacks (n=1092) were younger than whites (n=9530) and others (n=2105) (mean age: 50.3, 53.0 and 53.1, respectively, both p<.001), had fewer HLA matches (% of 6 matches: 8.9, 16.8, and 14.3, respectively, p<.001) and were more likely to be diagnosed with Hepatitis C (% diagnosed = 33.0, 29.0, and 28.0, respectively, p<.01). Before adjustment, blacks had nearly 60 percent greater hazard of graft failure compared to whites (HR [95% CI]: 1.58 [1.32-1.89], p<.001) while graft failure for others did not differ from whites (1.04 [0.88-1.22], p>.05). In a nested model, recipient age accounted for 5.7% of the excess risk among blacks. Adjusting for donor characteristics, greater donor age and ethnicity was associated with increased risk of graft failure. There was an increase risk of failure for recipients with donors greater than age 30 (HR [95% CI]: 1.48 [1.28-1.72], p<.001) and greater than age 60 (HR [95% CI]: 2.43 [2.03-2.91], p<.001) compared to those with donors <30 years of age. Recipients with Latino donors had an increased risk of failure compared to those with white donors. Having a black donor was not associated with increased risk nor was ethnicity mismatch between recipient and donor. Further, level of HLA mismatch was not associated with increased risk. Donor characteristics and/or mismatch did not account for the observed excess risk among blacks. CONCLUSION: We identified an excess risk of graft failure among blacks in a large nationally representative sample. Older age and having an older, Latino donor were additional risk factors. However, no factors measured in this study could account for excess risk among blacks. Studies exploring social, behavioral and biological mechanisms underlying disparities in transplant outcomes are warranted.
Clinical Presentation of Chronic Liver Disease in Germany: Role of Etiology, Age and Gender. A. Tromm, |J. Petersen, P. Buggisch, et al ABSTRACT FINAL ID: 776
BACKGROUND: Many patients (pts) with chronic liver disease are asymptomatic or may have nonspecific symptoms such as fatigue in the absence of hepatic synthetic dysfunction. Information regarding the presentation of chronic liver disease in Germany is still scarce. We investigated the frequency of asymptomatic and symptomatic presentations of chronic liver disease according to HCV status, gender and age. METHODS: Based on ALT/AST
screening between 12/2008 and 12/2010, 3161 pts with elevated liver enzymes were identified by 19 German hospitals and gastroenterological practices. Clinical presentations by symptoms (e.g. fatigue, pruritus) were retrospectively analyzed by gender, age and HCV status. Only pts with information on HCV status were included. Patients with liver cirrhosis were excluded from the analysis. RESULTS: Of 2400 pts with chronic liver disease N=1018 had chronic HCV infection while N=1382 suffered from HCV-negative chronic liver disease (NASH: N=699; alcohol: N=157; hepatitis B: N=143; autoimmune: N=80; PBC/PSC: N=62; genetic/metabolic: N=105; other: N=136). Liver disease was asymptomatic in 42.7% and 43.4% of pts with/without HCV and declined from 45.3% and 47.7% to 37.1% (p=0.013) and 31.9% (p<0.0001) in pts <50 years / >50 years. Fatigue was the most common symptom in both groups with a higher frequency of 49% compared to 34.7% in pts with/without HCV (p<0.001) and increased only
slightly with increasing age from 46.7% and 35.8% (<50 years) to 54.4% (p=0.02) and 40.6% (>50 years; p=0.10). In contrast, pts without HCV showed a 2-fold higher frequency of abdominal pain/discomfort (26.4%) compared to HCV patients (13.2%, p<0.0001) with a maximum of 34.2% in pts >50 years. In both groups the frequency of above symptoms together with pruritus and weak concentration did not differ between females and males while arthralgia
was more frequentin females than males with HCV infection (6.5% vs 2.9%, p<0.01).
CONCLUSIONS: The present study demonstrates a high frequency (>40%) of asymptomatic chronic liver disease in the German population. The frequency of symptoms seems to be determined by etiology of liver disease and age rather than by gender. Our results confirm a particularly high prevalence of fatigue in pts with chronic HCV infection.
Limiting Donors to Those of Younger Age in Hepatitis C infected Liver Transplant Recipients Does Not Increase Wait-list Time, Drop-out or Death. J.A. Flemming, C. Freise, F.Y. Yao, et al. ABSTRACT FINAL ID: 8
BACKGROUND: Donor age (DA) is the single most important donor factor influencing disease
severity and graft loss in liver transplant (LT) recipients with hepatitis C (HCV). With the goal of improving HCV outcomes, our institution actively restricted DA in HCV candidates to 50 years of age or less starting October 1, 2009. AIMS: To determine whether this practice of restricting DA among HCV candidates increased time on the waitlist (WL) or increased WL death/drop-out. METHODS: Patients listed for LT at our center between March 1, 2002 and
December 31, 2011 were identified using the United Network for Organ Sharing database. Three different time periods were compared to reflect events prior to and after DA restriction: Era 1: March 1 2002 – December 31, 2005 (DA risk unrecognized), Era 2: January 1 2006 – September 30, 2009 (no specific policy), and Era 3: October 1, 2009 – December 31, 2011 (DA restriction policy). Risk of WL death/drop-out according to the date of listing was examined using competing risks (CR) regression. Post-transplant survival was assessed with Kaplan Meier analysis. RESULTS: 1,145 patients (median age 56 yrs, 72% male, 8% African-American, 20% HCC exception) with HCV were listed for LT during this time; Era 1=518, Era 2=371, Era 3=256. 480 patients with HCV underwent LT during the observationperiod. Median donor age decreased significantly by Era, but median WL days did not change significantly in those
transplanted (table). Moreover, the sub-hazard for WL death/drop-out was lower in Eras 2 and 3 vs. Era 1, after adjusted for age, sex, HCC exception and MELD at listing,(table). Two-year post-LT survival was high, without significant differences between Eras (table). CONCLUSION: Our practice of DA restriction is not associated with significantly longer WL time, nor does it increase WL death/drop-out. Although we have not seen a change in post-LT
mortality with this policy, longer post-LT follow-up is needed before the true effect of DA restriction can accurately be estimated.
Incidence of hepatocellular carcinoma in precirrhotic and cirrhotic chronic B and C hepatitis: Systematic review with data from 39 trials and 10.231 patients. M. Thiele, L.L. Gluud, E.K. Dahl, et al. ABSTRACT FINAL ID: 524
INTRODUCTION: Chronic hepatitis B and C increases the risk of developing hepatocellular carcinoma (HCC). METHODS: We performed a systematic review on the incidence of HCC in treated and untreated patients with chronic hepatitis B and C in randomised controlled trials, prospective cohorts and case control series. Electronic and manual searches were combined (last update May 2012). HCC person-time incidence rates/100.000 person years were calculated with 95% confidence intervals using person years as the exposure variable and assuming a Poisson distribution for registered events (cases of HCC). Subgroup analyses in which patients were stratified by antiviral therapy and cirrhosis were performed. Calculations were performed in STATA version 11 (StataCorp, TX, USA). RESULTS: In total 10.231 patients from 39 trials and studies were included (randomised controlled trials, n=14 and prospective
cohort and case control studies, n=24). Among patients with hepatitis B, 3909 received antiviral therapy (interferon and/or nucleos(t)ides) and 3125 were controls (untreated). Among patients with hepatitis C,1804 received treatment (interferon alone or with ribavirin) and 1393 were controls (untreated). The HCC incidence in chronic hepatitis B was 757/100.000 person year in treated patients (95% CI 635-895; five year incidence 3.7%) and 1460/100.000 person year in untreated patients (95% CI 1289-1649; five-year incidence 7.1%). In subgroup analyses of patients with cirrhosis, the incidence rates were 2120/100.000 (95% CI 1573-2795; five year incidence 10.2%) for treated and 2763/100.000 person year (95% CI 2376-3194; five year incidence 13.1%) for untreated patients. Patients with chronic hepatitis C had a high risk of developing HCC. The HCC incidence was 1988/100.000 person year for treated (95% CI 1709-2299; five year incidence 9.6%) and 3101/100.000 person year for untreated (95% CI
2694-3553, five year incidence 14.6%). In subgroup analyses of patients with cirrhosis and chronic hepatitis C, the HCC incidence was 2687/100.000 person year in treated (95% CI 2261-3172, five year incidence 12.7%) and 4655/100.000 person year in untreated patients (95% CI 3941-5463; five year incidence 21.2%). CONCLUSION: Chronic hepatitis B patients without cirrhosis carry a low risk of HCC and the value of surveillance can be questioned. The risk is almost 100 fold in patients with cirrhosis and chronic hepatitis B. Both treated and untreated patients with HBV and HCV cirrhosis has a substantial risk of HCC.
Efficacy and safety of hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma. T. Yamashita, T. Terashima, K. Arai, H. et al. ABSTRACT FINAL ID: 577
BACKGROUND: In Japan, hepatic arterial infusion chemotherapy (HAIC) has been used to patients with advanced hepatocellular carcinoma (aHCC). In our department, interferon (IFN)-combined 5-fluorouracil (5-FU) continuous HAIC has been positively introduced to in aHCC. We analyzed efficacy and safety of IFN-combined 5-FU continuous HAIC retrospectively.
METHODS: Consecutive patients with measurable histologically or radiologically confirmed aHCC (major vascular invasion and/or bilobular multiple ≥5 nodules) were treated with following protocol: continuous 5-FU HAIC (300mg/m2 day1-5, day8-12) and IFN (IFN alpha-2b 3M IU, intramuscularly, 3 times per week for 4 weeks or pegylated IFN-alpha-2b 1.0μg/kg,
subcutaneously, every week for 4 weeks) was administrated with or without cisplatin (CDDP 20mg/m2 or DDP-H 18.8mg/m2, day 1, day 8). The treatment cycles repeated for 6 weeks with 2 weeks rest. Response rate (RR), tumor control rate (TCR), median survival time (MST), progression free survival (PFS) adverse events and factorial analysiswere performed. RESULTS:Two hundred thirty three patients (80% male, median age 65 yrs., 55% Child-Pugh class A, 35% Child-Pugh class B, 54% Hepatitis C, 66% recurrence, median tumor diameter 39 mm, 47% macroscopic vascular invasion, 18% extrahepatic spread) were enrolled. In all patients, RR was 27% (CR 5%, PR 22%) and TCR was 55%. Combination of CDDP increased RR but statistically insignificant (30.6% vs. 22%, p=0.16). Child-Pugh class was not affected to RR
(class A 33% vs. class B 26%, p=0.29). MST and PFS in all patients were 10.7 months and 3.2 months, respectively. MST of Child-Pugh class A patients was not differ to that of Child-Pugh class B (13.0 months vs. 9.1 months, p=0.15). PFS was also not different (4.3 months vs. 3.7 months, p=0.23). Factorial analysis (multivariate) revealed tumor diameter<5cm and albumin≥3.5g/dL as factors to predict RR. Moreover, ECOG-PS 0, macroscopic vascular invasion absent, distant metastasis absent, albumin≥3.5g/dL and AFP<400ng/mL were revealed as prognostic factors. Most frequently treatment induced Grade 3/4 adverse events (AEs) were hematological toxicity (thrombopenia 32%, neutropenia 31%, anemia 6%) and non-hematological toxicity (liver dysfunction 13%, nausea 11%, malaise 3%), but these AEs were controllable. CONCLUSION: HAIC using IFN and continuous infusion of 5-FU was effective to aHCC even in impaired hepatic reserve, Child-Pugh class B patients. This HAIC should be selected to intrahepatic aHCC patients who failed to sorafenib therapy because of adverse events or insufficient efficacy or patients who is inadequate to sorafenib therapy.
Disease Presentation and Treatment in Patients with Hepatocellular Carcinoma (HCC) Associated with Hepatitis B Virus (HBV/HCC) and Patients with Hepatitis C Virus Associated HCC (HCV/HCC) J.M. Wantuck, P. Lee, N.B. Ha, et al. ABSTRACT FINAL ID: 524
PURPOSE: Both HBV and HCV infection are common causes of HCC and each has distinct
epidemiology and clinical characteristics. HBV/HCC and HCV/HCC patients may also differ but data on this is limited. METHODS: A retrospective study was conducted to examine clinical characteristics of 1,110 consecutive patients seen between 01/1991 and 10/2011 at a U.S. university hospital with HBV/HCC (n=415) or HCV/HCC (n=695). RESULTS: Patients in both groups were similar in age (60±11years) and gender distribution (79% male). The majority
(87%) of HBV/HCC patients were Asian though 32% of HCV/HCC patients were also Asian (p<0.0001). HCV/HCC patients were more likely to have cirrhosis as compared to HBV/HCC (94% vs. 58%,p<0.0001). With regard to cancer staging, more HCV/HCC patients presented with stage A (46% vs. 41%,p<0.0001), while a larger proportion of HBV/HCC patients presented with Stage C/D disease (27% vs. 14%,p<0.0001) (Figure 1). Likewise, HBV/HCC
patients were less likely to meet Milan criteria (36% vs. 47%,p<0.0001). Compared to HCV/HCC patients, HBV/HCC patients were more likely to get partial hepatic resection (26% vs. 9%,p<0.0001) and less likely to undergo liver transplantation (LT) (6% vs. 15%,p<0.0001). On multiple logistic regression also inclusive of gender and MELD scores, negative predictors for LT were older age (OR=0.93, p<0.0001) and higher BCLC scores (OR=0.78,p=0.001)
while positive predictors were cirrhosis (OR=21.4, p=0.004) and non-Asian ethnicity OR=2.5,p=0.002). HCV is not an independent predictor for LT (OR=1.11,p=0.76). One-quarter of patients in both groups received only supportive care (25%). CONCLUSIONS: HBV/HCC patients presented with more advanced HCC though only half had cirrhosis. HBV/HCC patients were more likely to undergo hepatic resection but much less likely to undergo LT. Non-Asian ethnicity was a significant independent predictor for liver transplantation on multivariate analysis. Additional studies are needed to study factors contributing to the lower rate of LT in Asian HCC patients and high rate of supportive-care only patients in all groups.
Predictive factors for the development of hepatocellular carcinoma in chronic hepatitis C following sustained virological response to interferon therapy. M. Kurosaki, N. Izumi ABSTRACT FINAL ID: 998
BACKGROUND AND AIMS: Sustained virological response (SVR) to interferon (IFN) therapy could decrease the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis C. However, HCC still develop in some patients after achieving SVR. The aim of the present study was to define risk factors for development of HCC following SVR. METHODS: This was a nationwide multicenter study conducted by Japanese Red Cross Liver Study Group, involving 18 hospitals and medical centers. A total of 778 genotype 1b chronic hepatitis C patients who had SVR to IFN therapy from 1992 to 2009 were enrolled. Patients with past history of HCC were excluded. Median period of follow up was 5.7 years. RESULTS: The cumulative incidence of HCC was 0.9 % in 1-yr, 3.7 % in 3-yr, 6.5 % in 5-yr, and 10.9% in 7-yr, respectively. Cox regression analysis showed that age (hazard ratio (HR): 2.22, P=0.001), platelet counts (HR: 1.90, p<0.0001), AST levels (HR: 1.59, p=0.048), and alpha-fetoprotein (AFP) levels at 24 weeks after IFN therapy (HR:4.54, p<0.0001) were independent predictive factors for the cumulative development of HCC. For the prediction of HCC development within 5 years after IFN therapy, independent risk factors were older age (area under the ROC curve (AUROC) 0.740, p<0.0001, optimal cut-off: 60 years old), lower platelet counts (AUROC 0.698, p<0.0001, optimal cut-off: 150 (109/L)) and higher AST at 24 weeks after IFN therapy (AUROC 0.732, p<0.0001, optimal cut-off: (30 U/L). The hazard ratio of HCC development within 5 years was 61.5 in older patients with high AST and low platelet counts compared to younger patients having low AST and high platelet counts (95% confidence interval (CI): 8.58-543.2, p<0.0001). For the prediction of HCC development beyond 5 years, AFP levels at 24 weeks after IFN therapy was the sole significant factor (AUROC 0.720, p<0.0001). Using the optimal cut-off value of 5.0 ng/ml, the sensitivity and specificity to predict HCC development beyond 5 years was 60% and 73%, respectively. Compared to patients with AFP <5.0 ng/ml, the hazard ratio of HCC development beyond 5 years was 4.6 for those with AFP 5 to 10 ng/ml (95% CI: 2.13-9.76, p<0.0001), and 22.3 for those with AFP >10 ng/ml (95% CI: 9.01-55.02, p<0.0001). CONCLUSIONS: Predictive factors for development of HCC following SVR were older age, lower platelet counts, higher AST, and higher AFP levels at 24 weeks after IFN therapy. The optimal cut-off value of AFP for the prediction of HCC development beyond 5 years was as low as 5.0 ng/ml. Patients with these predictive factors may be the candidate for a careful HCC surveillance even after the complete eradication of hepatitis C virus.
Postoperative antiviral therapy with pegylated interferon plus ribavirin associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Y. Hsu, Y. Hsu, J. Lin, et al. ABSTRACT FINAL ID: 165
BACKGROUND: Hepatocellular carcinoma (HCC) commonly recurs after surgical resection without effective adjuvant therapy. Pegylated interferon plus ribavirin has been shown efficacious in preventing the development of hepatitis C virus (HCV)-related HCC, but its efficacy in reducing HCC recurrence remains unknown. Objective: We aimed to investigate whether postoperative antiviral therapy reduced recurrence of HCV-related HCC after resection. METHODS: This population-based retrospective cohort study analyzed the Taiwan National Health Insurance Research Database. After screening 17,574 patients undergoing liver surgery for a first-time diagnosis of HCC between October 2003 and December 2008, we identified 893 patients with antiviral-naïve HCV infection who had curative resection without recurrence within one year. Ninety five eligible patients received postoperative pegylated interferon plus ribavirin (treated cohort), and were matched 1:4 in age, gender, and cirrhosis status with 380 patients using no antiviral agent (untreated cohort). Patients were followed up for HCC recurrence and mortality since one year after surgery. RESULTS: The HCC recurrence rate was significantly lower in the treated than the untreated cohort (32.39% versus 47.69% after 3 years of follow-up, p=0.004). With adjustment for multiple confounders including death occurring prior to HCC recurrence, the recurrence risk was reduced nearly by half (hazard ratio 0.52; 95% CI, 0.34-0.80) among treated patients. Multivariate stratified analyses confirmed antiviral therapy was consistently associated with attenuated risk of HCC recurrence across subgroups. Moreover, mortality was lower in the treated cohort significantly (1.92% vs. 17.68% after 3 years of follow-up, p=0.004). CONCLUSIONS: Postoperative pegylated interferon plus ribavirin is associated with reduced recurrence of surgically resected HCV-related HCC. A. Recurrence of surgically resected hepatocellular carcinoma in patients without and without postoperative antiviral therapy; B. Mortality rates between the treated and untreated cohorts.
Outcomes in patients with small hepatocellular carcinoma and chronic hepatitis C infection treated with RFA and antiviral therapy. N.M. Kemmer, A. Alsina, G.W. Neff, et al. ABSTRACT FINAL ID: 592
INTRODUCTION: Hepatocellular carcinoma (HCC) is the third most common cause of death worldwide. The risk of developing HCC in patients suffering from cirrhosis is increased in the setting of chronic HCV. Objective: To determine the tumor recurrence, safety, and survival outcomes of HCC patients with chronic hepatitis C (genotype 1) infection after receiving radiofrequency ablation (RFA) and antiviral therapy using peg-alfa interferon and weight
based ribavirin. METHODS: Using our institution’s database, we identified all patients with chronic Hepatitis C (HCV) genotype 1 and small HCC (less than 3.0 cm) between December 2007 – December 2010. The following data was extracted; sustained virological rate (SVR), tumor necrosis rate and tumor recurrent rate, and 1-year survival rate. HCC recurrence and monitoring was done using serum a-fetoprotein (AFP) test and radiological findings. RESULTS: During the study period, there were 75 patients (42 males, 33 females, age 43 years (32-54) with HCC (≤3cm) and HCV (genotype 1). We divided the patients into two groups: control group (n=33) received RFA only and treatment group (n=42) received RFA and peg-alfa interferon with weight based ribavirin. The tumor complete necrosis rate at three months in the control group was 24.24% versus Rx group was 50% (P<0.05). The one-year viral suppression in the control group was 30.3% versus Rx group 64.28% (P<0.05). The HCC recurrence rate in the control group was 38.39% versus Rx group 7.1% (P<0.05). The one-year survival rate was 30.3% in control group versus Rx group 61.9% (P<0.05). CONCLUSION: The above results demonstrate potential benefits of adding antiviral therapy and suppressing HCV virus in patients with compensated cirrhosis and small HCC undergoing RFA. Further trials involving larger number of patients are needed to delineate the overall impact of HCV eradication in the patient with compensated cirrhosis and HCC. As the antiviral therapies continue to evolve future trials may offer an opportunity at viral eradication prior to LTx thus improving long term outcomes.
Liver stiffness as a predictor of hepatocellular carcinoma development in chronic hepatitis C patients receiving interferon-based anti-viral therapy. Y. Narita, T. Genda, H. Tsuzura, et al. ABSTRACT FINAL ID: 533
BACKGROUND AND AIMS: Many patients with chronic hepatitis C (CHC) receive interferon (IFN)-based antiviral therapy. Because it not only prevents progression to cirrhosis but also reduces the risk of hepatocellular carcinoma (HCC) development. However, HCC development is not rare after IFN therapy even in patients who achieve a sustained viral response (SVR). Assessment of the risk of HCC development is clinically important in the management of patients, but the risk factors for HCC development have not been established for patients receiving IFN therapy. Recent studies suggested that liver stiffness measurement (LSM), a procedure developed for the noninvasive assessment of liver fibrosis, has a predictive value for HCC development in cases of several kinds of chronic liver disease. We attempted to elucidate the usefulness of LSM for assessing the risk of HCC development in CHC patients who receive IFN therapy. METHODS: The study included 151 consecutive CHC patients who received IFN
therapy. All patients underwent percutaneous liver biopsy and LSM was performed using FibroScan® before IFN therapy was initiated. Univariate and multivariate Cox proportional hazard analyses were used to estimate the hazard ratios (HRs) of the clinical, viral and biochemical characteristics for HCC development. The cumulative incidences of
HCC development were evaluated using Kaplan-Meier plot analysis and the log-rank test. RESULT: During the median follow-up time of 600 days, 9 of the 151 patients developed HCC after IFN therapy. Univariate Cox proportional hazard analysis showed that age (HR 1.09, P = 0.038), LSM (HR 1.11, P = 0.001), platelet count (HR 0.81, P =0.006), and non-SVR (HR 9.32, P = 0.036) were associated with HCC development. Multivariate analysis identified 3
independent risk factors for HCC development: LSM (≥14.0 kPa, HR 5.58, P = 0.020), platelet count (≤14.0 × 104/μL, HR 5.59, P = 0.034), and non-SVR (HR 8.28, P = 0.049). Kaplan–Meier plot analysis showed that the cumulative incidence of HCC development at 3 years was 60%, 8%, and 0% in patients with all 3 risk factors, 2 or 1 of the 3 risk factors, and none of the 3 risk factors, respectively. The differences between the 3 groups were statistically significant
(P < 0.001). CONCLUSION: LSM-based risk assessment was successfully used to stratify the risk of HCC development in patients receiving IFN-based antiviral therapy. These results indicate the usefulness of LSM before IFN therapy for the management of CHC patients.
Hepatocellular Proliferation and Metabolic Syndrome Risk Factors are Increased in Non-Cirrhotic Hepatocellular Carcinoma: A Case-Control Study. B. Schlansky, Z. Jiang, K.D. Ingram, et al. ABSTRACT FINAL ID: 557
PURPOSE: Hepatocellular carcinoma (HCC) arising in the absence of underlying cirrhosis or hepatitis B (HBV) infection is increasingly recognized, particularly in hepatitis C (HCV) infected persons. We performed a casecontrol study to evaluate clinical and histologic characteristics associated with non-cirrhotic HCC. METHODS: Consecutive HBV-negative patients with pathologic diagnoses of HCC without background cirrhosis on resection were
retrospectively identified from 2005-2012. 4 control groups of 10 patients were selected – 1) cirrhosis with HCC; 2) cirrhosis without HCC; 3) less than stage 3 fibrosis, no HCC, HCV-positive; and 4) less than stage 3 fibrosis, no HCC, HCV-negative. Clinicodemographic characteristics were abstracted from the medical record. Hematoxylin and eosin (H&E) stains of non-HCC background liver were assessed by 2 pathologists for inflammation, fibrosis, and steatosis. Ki-67 immunohistochemistry was performed to assess proliferation, with stained hepatocyte nuclei counted by 2 blinded examiners from 20 high-power microscopic fields, and then averaged. RESULTS: We identified 26 patients with non-cirrhotic HCC; mean age was 65 years, with 62% male, 96% White race, 23% heavy alcohol users, 42% diabetic, 69% hypertensive, 31% obese, and 31% HCV-positive. H&E median inflammation grade was 1 (interquartile range (IQR) 0-1), fibrosis stage 1 (IQR 0-2), and steatosis score 1 (IQR 0-2). Compared to cirrhotics with HCC, the study group had less frequent alcohol use and obesity (p<.01), and less background inflammation (p<.01) and steatosis (p=.06). Compared to non-cirrhotic HCV-positive patients without HCC, the study group had more frequent hyper tension and hyperlipidemia (p<.01), but routine histology did not differ (p=.28-.31). Compared to non-cirrhotic HCV-negative patients without HCC, the study group had more frequent diabetes (p<.01), hypertension (p=.06), obesity (p=.04), and steatosis (p=.04). The non-cirrhotic HCV-negative group had low Ki-67 staining; otherwise Ki-67 staining did not differ between study and control groups (p=.45-.98). Among HCV-positive patients, Ki-67 staining was markedly increased in background liver of non-cirrhotic HCC patients compared to non-cirrhotic patients without HCC (p=.04). CONCLUSIONS: 1. Non-cirrhotic HCC patients display frequent metabolic syndrome risk factors despite having minimal steatosis. 2. Hepatocellular proliferation is increased in background liver of non-cirrhotic HCV-infected persons with HCC compared to those without HCC. Targeted HCC surveillance of non-cirrhotic HCV-infected persons with the metabolic syndrome or pronounced hepatocellular proliferation warrants investigation.
Impact of metformin on HCC prognosis in presence and absence of HCV infection
H.M. Hassabo, M. Iwasaki, K. Soliman, Y. et al. ABSTRACT FINAL ID: 547
BACKGROUND: Hepatitis C virus (HCV) is a known risk factor for hepatocellular carcinoma (HCC). Several studies showed that diabetes mellitus (DM) increases the risk of HCC; however the antidiabetic treatment with metformin can reduce the risk of HCC among diabetics. We aimed to assess the influence of metformin treatment on the overall survival of diabetic patients with HCC. METHODS: Between 2000 and 2012 total of 644 patients with pathologically confirmed HCC were prospectively enrolled in our clinical epidemiology study and each patient was personally interviewed for demographic and HCC risk factors. Participants reported their detailed history of DM including duration and type of treatment of the DM. Baseline clinical
information and prognostic factors were retrieved from the medical records. Median survival was estimated by using the Kaplan-Meier product-limit method, and significant differences between the survival times were determined by using the log-rank test. To identify independent prognostic factors for overall survival, hazard ratios (HR) and 95% CIs were calculated by using Cox proportional hazard models with a backward stepwise selection procedure. RESULTS: Total of 224 HCC patients had prior evidence of chronic HCV infection (34.8%) and 221 had prior history of diabetes mellitus (34.3%). DM was significantly common in patients without HCV infection (39.3%) than in patients with HCV-related HCC (25%), P =.001. Although we observed no statistical impact of DM on overall survival of HCC patients in presence and absence of HCV infection, HCC DM patients who were treated with metformin had longer
survival duration in presence of HCV infection (Median survival 30.3 months) as compared to non-metformin users (Median survival 16.5 months), p=.05 (Table 1). After adjustment for baseline clinical predictors of patients’ survival including staging, prior treatment, AFP, cirrhosis, age, sex, and race, the Cox regression analysis indicated 80% mortality reduction in the metformin users (HR=0.1-0.5) in HCV-induced, P=0.001. CONCLUSIONS: Metformin users among DM patients with HCC had a favorable survival compared with patients without metformin treatment. This observation was supported by recent study in patients with Radio-frequency ablation suggesting the significant anti-cancer and anti-inflammatory activity of metformin.Prognostic effect of metformin on HCC
Predicting the treatment efficacy of sorafenib in patients for hepatocellular carcinoma: a multi-center retrospective study in Japan. T. Yamashita, S. Kaneko, M. Kudo, K. Ikeda. ABSTRACT FINAL ID: 571
BACKGROUND: We performed a multi-institutional joint research in patients with advanced hepatocellular carcinoma to reveal the factors predicting the treatment effect to sorafenib in routine Japanese clinical settings. METHODS: An integrated database was created using individual patient data from 21 Japanese hospitals. Response rate, survival, adverse events and factors related to treatment effect were analyzed retrospectively. Antitumor effect was
evaluated by RECIST v1.1 criteria, and toxicity was graded according to the NCI CTC-AE v3.0. Factorial analyses were performed by Kaplan-Meier method, log-rank test, the Cox proposal hazard regression model, Fisher direct method and logistic regression analysis. RESULTS:
Three hundred eighty eight patients (79% male, median age 71 yrs, 76% Child-Pugh A, 23% Child-Pugh B, 62% Hepatitis C, 22% macroscopic vascular invasion, 51% extrahepatic spread) were enrolled. In the patients, 32% received reduced dosage less than 800mg daily. In all patients, median survival time (MST) and time to treatment failure (TTF) were 10.7 months and 2.1 months, respectively. Disease control rate (DCR) was 49% (CR 0.3%, PR 7% and SD 41%). Child-Pugh class B patients showed the tendency to inferior DCR (48% vs. 43%; p=0.058), MST and TTF were shorter than class A patients (MST: 6.4 months vs. 11.7 months; p<0.01, TTF: 1.4 months vs. 2.1 months; p=0.043). Initial dosage of treatment did not have any effect on DCR, MST and TTF. Factorial analysis (univariate) revealed ECOG-PS 0, maximum tumor diameter <3cm, albumin≥3.5g/dL, alphafetoprotein (AFP)<100ng/mL and des-gamma-carboxy prothrombin (DCP)<400mAU/mL as factors to predict DCR. Multivariate analysis revealed albumin and AFP as predictive factors. Moreover, ECOG-PS 0, Child-Pugh class A,
maximum tumor diameter <3cm, albumin>3.5g/dL and AFP<100ng/mL were revealed by univariate analysis, and finally tumor diameter was extracted as factors related TTF. Most frequently drug induced Grade 3/4 adverse events were hand-foot skin reaction (HFSR) (10%), hypertension (10%), diarrhea (4%), and anorexia (4%). CONCLUSIONS: Sorafenib is effective in Child-Pugh class A patients of advanced hepatocellular carcinoma in Japan. Several clinical
factors associated to treatment efficacy of sorafenib may help to select the beneficial patients to sorafenib.
Hepatocellular carcinoma: Ethnic disparities in viral etiology. The Harlem Experience
Y. Siba, J. Kretchy, A. Gupta, J. Culpepper-Morgan. ABSTRACT FINAL ID: 608
BACKGROUND: Hepatocellular carcinoma (HCC) is the most rapidly increasing cancer in the U.S. The prevalence of hepatitis B and C in HCC in the U.S is approximately 18% and 29% respectively. Harlem Hospital, NY serves a demographically unique community of color with 45% African Americans (AA), 35% Hispanic Americans (HA), 10% African immigrants (AI) and 10% others. METHOD: A retrospective cohort review was done to describe the epidemiology and clinical characteristics of patients with primary HCC seen at Harlem Hospital between Jan 2000 and Dec 2010 (n=46). RESULTS: Seropositivity for HCV was 70% (32/46) and 26% (12/46) for HBV in patients with HCC. 6.5% (3/46) were coinfected with HBV. In 4.3% (2/46) the etiology of HCC was undetermined, p<0.0005 vs. U.S average. The average
age was 61 years, range 38-85. 75% (35/46) were male. The racial background for HBV-related HCC was 75% (9/12) AA, 8.3% (1/12) HA, and 16.7% (2/12) AI. Whereas for HCV-related HCC, it was 75% (24/32) AA, 12.5% (4/32) HA and 12.5% (4/32) AI. HBV-related-HCC occurred at a younger age (52 years, ±9.5 SD) than HCV-related-HCC (61years, ± 9.4 SD), p = 0.007. 26% (8/32) HCV patients had positive HBcAb. The prevalence of cirrhosis in the HBV
group was 58.3% (7/12) and 81.3% (26/32) in the HCV group. Thrombocytosis, which has been associated with large tumor volumes and adverse outcome was less common in women with HCC 30% (3/10) than men 70 % (7/10) p=0.0069 and HBV more than HCV 33% (4/12) vs. 15.6% (5/32), p=0.0263. HCC without cirrhosis occurred in 33% (4/12) of HBV compared to 18% (6/32) of HCV, p= 0.045. Only 26% (12/46) were followed up in the GI – Hepatology
Clinic for HCC surveillance prior to diagnosis. The mortality rates for HBV and HCV related HCC were 83.3% and 70.3% respectively. CONCLUSIONS: The seroprevalence of HBV and HCV in HCC was significantly higher in our cohort (26% vs. 70%) than the national average (18% vs. 29%). African Americans were over represented in our cohort whereas Hispanic
Americans were under represented. There were no Caucasians or Asians in our cohort. The HBV related HCC patient was more likely to be young, non- cirrhotic, and have thrombocytosis than the HCV patient. A significant proportion of HCV patients had evidence of prior HBV exposure. We conclude that there is increased need for HCC surveillance among HBV and HCV patients in the African American population.
HCC in HCV patients without cirrohis: absence of associated NASH. B.K. Kutala, P. Bedossa, T. Asselah, L. et al. ABSTRACT FINAL ID: 1008
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) in absence of cirrhosis in chronic hepatitis C is rare and risks factors are not well known. Recently only 6 cases of HCC in the absence of cirrhosis related to VHC have been reported (Kathryn et al, World J Gastroenterol 2010). The aim of this study was to characterize the clinicopathological features of characteristics and frequency of patients with HCV-HCC without cirrhosis. We report here 15 cases. METHODS: The records of consecutive patients admitted for HCC with a positive HCV RNA and hospitalized in the hepatology or digestive surgery between January 2000 and December 2010 were identified by our registry hepalist and reviewed retrospectively with collection of 96 variables (data demographics, history and etiology of cirrhosis, circumstances of diagnosis, therapeutic management and survival). Inclusion criteria HCC and cirrhosis or noncirrhosis diagnosed by liver biopsy. Criteria of exclusion: (HCC and cirrhosis or non-cirrhosis diagnosed by other method than liver biopsy), patient treated for HCV infection, had other coexistent causes of cirrhosis or liver disease than HCV or Coinfection HBV or HIV.
RESULTS: 437 patients have been admitted for HCV-HCC during the period 2000-2010. Only 15 patients have HCVHCC without cirrhosis and 46 patients had HCV-HCC with cirrhosis satisfied to inclusion criteria. Finally 61 patients were studied (80% men). The median follow-up was 28 months (range: 1-143). The median age at diagnosis of HCC was 62 years in Cirrhosis group vs 69 in Non-Cirrhosis group. Abnormal AST, albumin, bilirubin total, platelets count,
were more frequent in cirrhosis group than in non-cirrhosis group (2.7 vs 1.5 xN, 35 vs 42 g/l, 22 vs 13 μmol/L, 114 vs 218 x10*/L (0.0006, 0.0002, 0.002, <0.0001). Steatosis and NASH were significantly more frequent in cirrhosis group than non-cirrhosis group (48% vs 13% and 19% vs 0% respectively P=<0.0001 and <0.0001). Markers of HBV active infection were significantly less frequent in cirrhosis group than in non-cirrhosis group ( Anti Hbc and Anti Hbs 5% vs
33% and 5% vs 26% p=<0.0001) CONCLUSIONS: Clinicopathological characteristics of HCV-infected patients with HCC with or without cirrhosis are different. Risk factors such as NASH, steatosis or overload hemosiderin was not found in patients without cirrhosis.
These results suggest a possible occult infection to HBV virus or a past infection to HBV virus may induce the HCC in the setting of HCV without cirrhosis that requires further investigation in the future.
Efficacy and safety of aggressive antiviral treatment for recurrent hepatitis C after liver
transplantation.Influence of Receptor and Donor Interleukin 28B Polymorfisms in virological response. J. Pascasio, J. Sousa, M. Ferrer, et al. ABSTRACT FINAL ID: 702
AIMS: To evaluate sustained virological response (SVR) and safety of antiviral treatment in liver transplant (LT) recipients with recurrent hepatitis C virus (HCV) infection, following a schedule starting with full doses of Pegylated interferon alpha-2a (PEG2a) plus ribavirin (RBV) and prolonging therapy in patients without rapid virological response (RVR) and to assess the influence of receptor and donor interleukin-28B (IL28B) polymorfisms in response. METHODS: Retrospective study of all liver recipients with histologically proven recurrent hepatitis C treated with full doses of PEG2a plus RBV for 48 (genotypes 1-4) or 24 (genotypes 2-3) weeks.We offered to prolong the therapy to 72 (genotypes 1-4) or 48 weeks (genotypes 2-3) to patients without RVR.There were 71 cases [(5 severe acute hepatitis and y 66 chronic hepatitis, 50% of which had advanced fibrosis (stage F3-F4)],80% genotype 1 and 69% with HCV-RNA≥800.000 IU/mL. 22 patients (19 genotype 1) received prolonged treatment. Genotyping of L28Brs12979860 was performed by TaqMan 5 allelic discrimination assay in 68 recipients and 66 donors (in liver biopsies obtained before initiating antiviral treatment). RESULTS: 29%,62%,68% and 58% (56% in genotype 1) of patients achieved HCV-RNA (-) at 4 weeks (RVR),12 weeks,end-of-treatment and SVR, respectively.SVR was associated to HCV-RNA (-) at 4 (90% vs 47%;p=0,001) and 12 weeks (84% vs 17%;p<0,0001) and to early virological response (70% vs 9%;p<0,0001).In patients without RVR, prolonged treatment tended to enhance SVR (82% vs 50%;p=NS) and reduce relapse (18% vs 33%;p=NS). RVS was associated to low virological load (82% vs 47%;p=0,009),but not to the severity of fibrosis. SVR was higher in recipients with IL28B CC and CT genotypes as compared with those carrying TT (67 and 69% vs 25%; p=0,016 and p=0,01,respectively) and also in donors (in liver biopsies) with IL28B CC and CT genotypes as compared with those carrying TT (66 and 62% vs 29%;p=0,01 and p=NS,respectively). Anemia, neutropenia, thrombocytopenia and rejection were observed in 83%, 60%, 24% and 22% of patients, respectively.Filgastrim, erythropoietin and transfusion were administered to 11%, 62% and 22%, respectively.21% of patients had to discontinue treatment for adverse events and this was associated to lower SVR (33% vs 64%;p=0,041). CONCLUSIONS: The aggressive treatment of recurrent hepatitis C after LT starting with full doses of PEG2a plus RBV and prolonging therapy in patients without RVR improves SVR as compared with previous reports.IL28B rs12979860 TT genotype in recipients and donors (in liver biopsies) are associated to lower SVR, without differences between CC and CT genotypes.
Efficacy and safety of protease inhibitors for hepatitis C recurrence after liver transplantation: a first multicentric experience. A. Coilly, B. Roche, T. Antonini, D. et al. ABSTRACT FINAL ID: 9
BACKGROUND: Protease inhibitors (PI), telaprevir and boceprevir, in combination with peginterferon/ribavirine improved sustained virological response rate in HCV genotype 1 patients (pts), naive or previously treated with dual therapy. We describe for the first time their use after liver transplantation (LT) for HCV recurrence on the graft. Patients and METHODS: This cohort study enrolled 25 liver transplant pts (male: 92%, mean age 54±11 years [31-75]),
with an active genotype 1 hepatitis C, in 5 centers between March 2011 and February 2012 and treated with boceprevir (n=14) or telaprevir (n=11) immediately or after a 4-weeks lead-in phase (n=21). The meantime between LT and PI initiation was 49.5±52.3 months [1.6 to 180]. Indication for therapy was HCV recurrence defined by ≥ F2 in the METAVIR scoring system (n=21) or a cholestatic hepatitis (n=4). Eleven (44%) pts were naive and 11 (44%) nonresponders
to a previous course of dual therapy after LT. Fifteen pts received cyclosporine (60%), 10 tacrolimus (40%). RESULTS: The mean follow-up was 20.3±8.8 weeks [2-40]. At baseline, HCV viral load, total bilirubin and hemoglobin levels were 6.86±1.17 log10 IU/mL [3.11 to 8.49], 50.9±95.7 μmol/L [5-372], 13.2±1.8 g/dL [8.7-16.3] respectively. After 4 weeks of PI, a rapid virological response was obtained for 6 (43%) boceprevir pts and 5 (45%) telaprevir pts.
After 12 weeks of PI, a complete early virological response was obtained for 11 (79%) boceprevir pts and 8 (73%) telaprevir pts. 6 pts experienced an early discontinuation of therapy, 5 for a virological breakthrough (boceprevir n=2, telaprevir n=3) and a null non-responder in the boceprevir group. Three severe infections occurred, leading to death in two pts (boceprevir: 1 at week 20; telaprevir: 1 at week 2). The most common side effect was anemia in 64% of pts:
92% and 91% in boceprevir and telaprevir groups received erythropoietin (EPO) alone or combined with ribavirin reduction and 4 pts received red blood cell transfusions. The cyclosporine dose was reduced by 1.5±0.4 fold [1.0 to 2.0] and 2.8±1.1 fold [1.3-4] with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.8±2.8
fold [3.1-9.5] and 40.0±14.8 fold [21.4-57.1with boceprevir] and telaprevir, respectively.
CONCLUSION: A complete early virological response after 12 weeks of triple therapy was observed in 76% of liver transplant pts in our cohort. More than 90% pts used EPO for anemia which was the most common adverse event. Interactions between PI and calcineurin inhibitors were constant but easily managed thanks to a close monitoring. Final results will be presented.
Multicenter Preliminary Experience Utilizing Boceprevir with Pegylated Interferon and Ribavirin for Treatment of Recurrent Hepatitis C Genotype 1 after Liver Transplantation.
B. Aqel, E.J. Carey, T.J. Byrne, et al. ABSTRACT FINAL ID: 706
BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplant is universal and causes significant reduction in both graft and patient(pt) survival. The use of protease inhibitors combined with pegylated interferon (PEG) and RBV significantly improve sustained virological response in non-LT patients. There is limited experience regarding their use post LT. AIM: To describe our experience with boceprevir-based triple therapy for recurrent HCV post LT
METHODS: Multicenter study describing the outcome of HCV treatment post LT, utilizing a strict and standardized clinical protocol. All pts were converted to cyclosporine based immunosuppression (IS) regimen prior to treatment. cyclosporine dose was halved and levels were closely monitored once boceprevir was initiated. All pts had a lead-in phase with PEG and RBV for 4 weeks followed by addition of boceprevir. Demographic, clinical, biochemical and
virological data was collected at baseline and during therapy. Ribavirin levels were monitored every 4 weeks RESULTS: Total of 23 patients with genotype 1 recurrent HCV were treated with boceprevir bases regimen between 06/11-04/12. Treatment characteristics are shown in table-1. Ten patients (43%) achieved complete early virological response; four of them continue to be negative at week 24. Six (26%) met the futility rules with inadequate virological
response. Treatment was stopped in four patients (17%)due to adverse events. All patients required growth factors support on treatment. CONCLUSIONS: Boceprevir based triple therapy can be used post LT but requires close clinical monitoring. Antiviral efficacy of this regimen is better than standard therapy in difficult to treat population. Patients should be closely
monitored for adverse events. Ongoing follow up will provide additional data regarding safety and efficacy of this regimen.
First ever successful use of Daclatasvir and GS-7977, an Interferon-free oral regimen, in a liver transplant recipient with severe recurrent Hepatitis C. R.J. Fontana, M.Bifano, D. Dimitrova, et al. ABSTRACT FINAL ID: 694
BACKGROUND: Recurrent HCV infection is nearly universal in liver transplant (LT) recipients and associated with an accelerated rate of allograft injury and fibrosis. Daclatasvir (DCV), a potent oral NS5A replication complex inhibitor, has synergistic antiviral activity and a favorable safety profile when combined with GS-7977, a potent oral nucleotide polymerase inhibitor. The aim of our study is to describe the first ever use of DCV and GS-7977 combination therapy in a LT recipient with severe recurrent HCV. METHODS: DCV 60 mg QD and GS-7977 400 mg QD were given for 24 weeks. Serum HCV RNA levels were assessed at weeks 0, 1, 2, 3, 4, 8, 12, 24 and at weeks 4, 8, 12, and 24 post-therapy (Roche Cobas Taqman, llod < 43 IU/ml). RESULTS: A 56 year old African-American male with diabetes and HCV genotype 1b failed to respond to IFN monotherapy as well as pegIFN and ribavirin combination therapy. Due to progressive liver failure, he underwent LT with a MELD score of 24. He initially did well
but at month 4 postLT developed elevated serum ALT and alk phos levels while on tacrolimus and prednisone. A liver biopsy at 6 months postLT demonstrated moderate chronic active hepatitis with cholestatic features and an Ishak fibrosis score of 4. He then developed ascites with serum AST 178 IU/ml, alk phos 316 IU/ml and bilirubin 4.1 mg/dl but normal creatinine. ERCP and inferior venocavagram were negative, HCV RNA was 12,000,000 IU/ml and IL28-B
genotype was CT. At month 8 postLT, DCV and GS-7977 were initiated and HCV RNA became undetectable along with normalization of liver biochemistries at week 4. By week 8, ascites had resolved and he remained HCV RNA negative throughout treatment. At post-treatment week 12, HCV RNA remains undetectable and liver biochemistries are normal. The tacrolimus dose and trough levels were unchanged during and after therapy. CONCLUSIONS: An interferon free regimen of DCV and GS-7977 led to rapid suppression of serum HCV RNA and sustained clearance of HCV in an immunosuppressed LT recipient who had previously failed pegIFN /ribavirin therapy. The potent antiviral efficacy and favorable safety profile of this Interferon-free oral combination regimen as well as the low potential for drug-drug interactions with calcineurin inhibitors make it an attractive regimen worthy of further study in LT recipients
Early and End of Treatment Virologic Responses in Patients with Hepatitis C (HCV) genotype I Recurrence After Liver Transplant Treated with Triple Therapy using Telaprevir: A Single Center Experience. P.S. Mantry, C. Wu, J.S. Weinstein, et al. ABSTRACT FINAL ID: 712
BACKGROUND: We report the first experience of treating a cohort of patients with HCV genotype I recurrence after liver transplant using off label telaprevir (TVR) based triple therapy in patients on Tacrolimus (TAC) based immunosuppression. METHODS: Since June 2011, we have treated 17 patients with genotype 1 HCV infection recurrence post liver transplant using combination therapy with pegylated interferon alpha 2a or 2b, Ribavirin (RBV), and TVR folowed by PEG/RBV combination therapy for additional 12 or 36 weeks. All patients were on TAC at a stable dose prior to start of the antiviral regimen. At the start of therapy, the TAC dose was reduced to approximately half the pre-treatment dose and the frequency was reduced to once a week with frequent level checks . After completing TVR, TAC was reintroduced slowly to pre-TVR dosing. CBC, Chemistry, HCV RNA, TAC levels and clinic evaluation of patients was
performed once a week during the first 4 weeks of Rx and every 2 weeks there after. RESULTS: There were 9 male and 8 female patients in the cohort who were from 6 months to 8 years out post transplant. 11/17 patients were genotype 1a. Of the 17 patients, 6 had rapid virologic response and extended (e)RVR; additionally 6 patients became aviremic at 32,33,40,55,62 84 and 90 days and had complete early virologic response. 4 patients were non responders and 1 patient had a breakthrough during treatment. 4 patients received response guided therapy and stopped at 24 weeks; the other 6 patients are still on therapy. Anemia was the most prominent side effect of treatment with all patients requiring growth factor support and 8 of them needing blood transfusions despite lower doses of RBV. CONCLUSIONS: We report the first experience of treating HCV recurrence in post liver transplant recipients with TVR based triple therapy in setting of TAC based immunosuppression. We observed robust virologic responses in a majority of patients and TAC/TVR interactions and side effects were manageable. Our preliminary data show that this treatment shows promising virologic responses in patients and merits prospective evaluation.
Liver transplant center focused experience with peginterferon alfa-2a, ribavirin and telaprevir therapy in patients with genotype 1 hepatitis C cirrhosis. J.F. Gallegos-Orozco, A.E. Chervenak, E.J. Carey, et al. ABSTRACT FINAL ID: 53
AIM: To describe our experience with direct acting antiviral (DAA) therapy for HCV genotype 1 cirrhotics, and to assess baseline features that may help identify patients at risk of severe adverse events. METHODS: Retrospective review of HCV-cirrhotic patients (baseline MELD ≤15) treated with telaprevir-based DAA. Demographic, clinical, biochemical and virologic data was collected at baseline and during therapy. Statistical analysis included descriptive statistics, chi square for categorical variables, T test or Wilcoxon test for continuous variables. Results reported as mean±standard deviation or median with interquartile range (IQR). P <0.05 defined statistical significance. RESULTS: 39 patients (9 on the liver transplant wait-list) with genotype 1 HCV-cirrhosis treated with telaprevir-based DAA between 6/1/2011-5/31/2012 at our liver transplant center. Gender: 27 men (69%)/12 woman (31%); mean age 55.3±6.4 years. HCV genotype: 1a 41%, 1b 28%, 1 without subtype 31%. IL28B polymorphism: CC 21%, CT 63%, TT 16%. Prior therapy experience: naïve 33%, relapser 23%, non-responder 38%, unknown 5%. Use of growth factors: erythropoietin 67%, filgrastim 46%. Treatment duration: mean 19.4±9.8 weeks. Thirty patients have completed 12 weeks of therapy, 24 have attained complete early viral response (80%), and 10 met criteria for extended rapid virologic response (33%). Currently 17 patients have completed 24 weeks of treatment, 10 (59%) have maintained undetectable HCV RNA. In 9/39 patients (23%) therapy was discontinued due to severe adverse events, including 4
patients with infectious complications requiring hospitalization (1 each: spontaneous bacteremia, severe bacterial pneumonia, renal abscess, diskitis with paravertebral abscess). No deaths have been recorded, but 1 patient suffered severe decompensation requiring liver transplant. In comparison with patients who did not develop severe complications, those who did had a higher baseline MELD (median 10, IQR 9-10 vs. 8, IQR 7-9, p=0.04) and lower platelet count (72±17 vs. 114±55, p=0.001). Other clinical, laboratory and viral features were similar between groups.
CONCLUSIONS: DAA treatment of cirrhotic patients is feasible but at the risk of increased frequency of serious adverse events, in particular severe infectious complications, requiring hospital admission and/or discontinuation of antiviral therapy. Cirrhotic patients in whom therapy is being considered require close clinical monitoring and high index of suspicion for bacterial infection if clinical decompensation occurs while on treatment. Our observations support that these patients should be treated in the context of a liver transplant center.
Dose Reduction Of Ribavirin To 200 mg Is Associated With Treatment Failure In The Treatment Of Null Responders Post OLT With Advanced Fibrosis/Cholestatic Hepatitis C With Telaprevir Plus PEG Interferon/Ribavirin. P.Y. Kwo, M. Ghabril, M.A. Lacerda, R. ABSTRACT FINAL ID: 719
Aggressive recurrence of hepatitis C remains problematic post OLT with low SVR rates with
PEGIFN/RBV (PR). There are limited data on treatment of G1 HCV infection with DAA therapy with PR post OLT and there are substantial drug-drug interactions with telaprevir(TVR)/ calcineurin inhibitors.Our AIM was to review our experience with TVR addition to PR in treatment of aggressive hepatitis C in null responders to PR post OLT. METHODS: Adult patients with recurrent HCV infection post OLT with null response to PR for 12 weeks (< 2 log
reduction) received 4 week lead-in PEG-IFN alfa-2b (1.0 μg/kg/wk) plus RBV (600-1000 mg/day) followed by addition of telaprevir 750 q8. All patients not on cyclosporine (CYA) were converted to CYA from tacrolimus prior to initiation of HCV therapy. On day 1 of TVR, patients received 25 mg CYA with trough levels titrated to 100 ng/ml. HCV RNA measured every 4 weeks by Cobas TaqMan HCV Test. RESULTS: Seven patients (3 M, 4 F), mean age 56 years, have been treated. 3 were < 1 year post-OLT, 6 had cirrhosis/1 bridging fibrosis. Treatment parameters are described in table. All patients required RBV dose reduction, 6/7 required EPO, 5/7 required G-CSF, 2/7 required eltrombopog for platelets <25,000 μl. Mean PRBCs transfused per patient was 8 over 12 weeks of TVR, mean PRBCs after TVR is 4. 2/7 individuals required hospitalization for severe anemia. All patients who achieved futility during TVR treatment or
breakthrough post TVR required RBV dose reduction to 200 mg due to anemia. One patient who reached futility at week 4 of TVR therapy continued PR with undetectable HCV RNA at week 28. No supra/sub-therapeutic CYA levels encountered, no episodes of renal insufficiency due to CYA toxicity. CONCLUSIONS: Conversion to CYA followed by four week PR lead-in with addition of telaprevir can lead to significant clearance rates at week 24 in null responders with advanced fibrosis though high rates of anemia/RBV dose reduction, growth factor, and transfusion require-ments were noted. Dose reduction of RBV to 200 mg was associated with treatment failure. CYA Interactions were easily managed by CYA dose adjustment. EOT results will be available for ¾ individuals who are HCV RNA undetected at week 24 by 11/2012.