Sa1059

The Experience With Telaprevir Based HCV Therapy in Community PracticeDoes Not Mirror the Clinical Trials DataLakshmi N. Potakamuri, Paul J. Thuluvath, Sergey Kantsevoy, Anurag Maheshwari

Background: Telaprevir based triple therapy for HCV (hepatitis C virus) infected genotype1 patients is now the standard of care as recommended by AASLD. Aims: To evaluate thecomplexity & morbidity of telaprevir based triple therapy for treatment of HCV. Methods:A retrospective review of 105 pts with HCV genotype 1, treated with telaprevir based tripletherapy in a community based practice. All patients completed at least 12 weeks of therapyunless treatment was discontinued per futility guidelines or due to adverse events. Patientswith cirrhosis Child class B/C, HIV co-infection, and patients after liver transplantation wereexcluded from the study. Results: The demographic data of all patients are listed in table1. A majority of patients were African-American, suffered from advanced fibrosis, hyperten-sion and genotype 1a infection. 62% of all patients had received prior interferon basedtherapy for HCV. The on-treatment progress, viral loads, discontinuation rates and seriousadverse events are listed in table 2. Since, the treatment outcomes of a significant numberof patients remain pending; this study does not aim to evaluate the efficacy of the abovetherapy. Adverse events experienced during treatment included anemia (n=74, 70%), fatigue(n=57, 54%), skin rash (n=50, 48%), pruritus (n=34, 32%), depression and anxiety (n=30,29%), anorectal discomfort (n=23, 22%) and retinopathy (n=4, 4%). The skin rash wasnoted to be mild (n=27, 26%), moderate (n=14, 13%) or severe (10, 10%), with 2 patients(2%) experiencing DRESS (drug rash with eosinophilia and systemic symptoms). Amongpatients that developed anemia (n=74), 16 (15%) were treated with erythropoietin stimulatingagents (ESA), and 29 (28%) required ribavirin dose reductions. 14 (13%) patients discontin-ued telaprevir prematurely due to adverse events. Seventeen (16%) pts were hospitalizedduring treatment for anemia (n=9, 9%), rash (n=3, 3%), hepatic encephalopathy (n=1, 1%),hyponatremia (n=1, 1%), sepsis (n=1, 1%), and dehydration (n=2, 2%). 12 (11%) ptsrequired blood transfusions with four patients requiring more than one transfusion. Onepatient died from septic shock during treatment. Conclusions: Real world community basedtreatment of HCVwith telaprevir based regimen carries a significantly higher rate ofmorbidity,relapse, treatment failure and serious adverse events than those published in the phase 3trials. This can result in a considerable increase in treatment complexity and potentiallyhigher costs. These data suggest that telaprevir based therapy should be implemented in asetting equipped to handle the complexity of current therapy for treatment of HCV genotype1 patients.Table 1. Demographic Data (n=105)

Table 2. On Treatment Data (n=105)

S-985 AASLD Abstracts

Sa1060

The Hematologic Effects of Pegylated Interferon, Ribavirin, and Boceprevir orTelaprevir: A Single Center ExperienceEric Martin, Tom C. Fang, Ken Christensen, Kristin Granlund, Leanne Graf, MeganGrischeau, Jane Christianson, Susan M. Harrold, Stacie Koole, Jose Franco, SamerGawrieh, Syed Rizvi, Veronica TenCate, Kia Saeian

Background: Virologic cure may diminish fibrosis in patients with chronic hepatitis C virus(HCV) infection while reducing liver-related morbidity and mortality. HCV treatment wasrevolutionized by addition of direct-acting antiviral agents (DAAs) - boceprevir (BOC) andtelaprevir (TVR) - to pegylated interferon α-2a/b (Peg-IFN) and ribavirin (RBV) by improvingcure rates across all stages of hepatic fibrosis in patients with genotype 1 HCV. However, thefive phase III DAA trials published present limited experience on management of hematologicparameters in cirrhotics. Aims: 1) Compare hematologic effects of Peg-IFN, RBV and DAAsbetween cirrhotics and non-cirrhotics treated for HCV. 2) Compare need for dose-reducedRBV, erythropoietin, blood transfusions, granulocyte colony stimulating factor (G-CSF) anddose-reduced Peg-IFN between cirrhotics and non-cirrhotics. 3) Compare treatment response[rapid virologic response (RVR) and sustained virologic response (SVR)] between cirrhoticsand non-cirrhotics. Methods: Longitudinal chart review of prospectively collected data per-formed on 125 consecutive patients treated with Peg-IFN, RBV and BOC (n=29) or TVR(n=96) from 5/2011 to 11/2012. Chi-squared and Fischer's exact tests used for comparison.Results: Interim analysis revealed 19/29 (66%) treated with BOC had fibrosis stage 3-4compared to 57/96 (59%) treated with TVR had fibrosis stage 3-4 (p .0.05). There wereno significant differences in number of patients who received .1 dose-reduced RBV, erythro-poietin, blood transfusion, G-CSF or dose-reduced Peg-IFN between cirrhotics and non-cirrhotics in either the BOC or TVR treatment group (p.0.05). A trend of lower hemoglobin(Hgb) seen in BOC-treated cirrhotics compared to stage 0-2 and to TVR stage 0-4 [Figure].Likewise, there is trend of higher Hgb in TVR-treated patients with stage 0-2 compared tostage 3-4 and to BOC stage 0-4. 9/29 (31%) treated with BOC completed therapy, 13/29(45%) actively receiving treatment and 7/29 (24%) stopped early (lack of response or dueto side effects). 20/29 (69%) BOC achieved RVR [9/10 (90%) stage 0-2 vs 11/19 (58%)stage 3-4; p.0.05]. 39/96 (41%) treated with TVR completed therapy, 15/96 (16%) activelyreceiving treatment and 42/96 (44%) stopped early. 76/96 (79%) TVR achieved RVR [34/39 (87%) stage 0-2 vs 42/57 (75%) stage 3-4; p .0.05] [Table]. Conclusions: Overall,hematologic response to Peg-IFN, RBV and BOC or TVR was no different between cirrhoticsand non-cirrhotics in our group. Although RVR data in cirrhotics was not statistically lower,there is a trend to lower RVR particularly in cirrhotics treated with BOC. The availabilityof SVR data at the time of the meeting will allow us to make more definitive conclusions.Our experience suggests that the hematologic effects of Peg-IFN, RBV and DAAs do notpreclude cirrhotics from treatment of chronic HCV.

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Hemoglobin Response to Pegylated Interferon, Ribavirin, and Boceprevir or Telaprevir

Sa1061

Similar GI Side Effects With Once-Daily Versus Twice-Daily Dosing Ribavirinin HCV-Positive Patients on Triple TherapyKian Bichoupan, Valerie Martel-Laferriere, Michel Ng, Andrea D. Branch, Douglas T.Dieterich

BACKGROUND: Ribavirin (RBV) is part of triple therapy for HCV infection. RBV is approvedfor twice-daily (divided) dosing, but its long half-life should allow once-daily dosing unlessthis increases toxicity and/or side effects. AIM: To assess side effects of twice-daily (2x/d)vs. once-daily (1x/d) RBV dosing during triple therapy. METHODS: A structured interviewwas used to collect information from 74 subjects whose medical records were also reviewed,with IRB approval. Patients provided data about RBV dosing, changes in dosing over time,dosing preferences, and Gl side effects (nausea, diarrhea, and vomiting). RESULTS: Fifty-eight patients were on telaprevir-based and 16 patients were on boceprevir-based tripletherapy; 71 took 180 μg peg-IFN, 3 took 135 μg peg-IFN, all took weight-based RBV ( ,61kg, 800 mg/d; ,75 kg, 1000 mg/d; ≥75 kg,1200 mg/d). Mean age was 57 yr (SD=9.3); 32had advanced fibrosis/cirrhosis. Median duration of treatment was 25 wk (range 8 to 48).AEs were frequent and often severe: 10 patients had an ER visit, 11 were hospitalized, 7were transfused, and 34 took EPO. Among the 74 patients, 35 (47%) had nausea, 13 (18%)had vomiting, and 25 (34%) had diarrhea. Importantly, among 9 patients on full-dose RBVwho switched from 2x/d to 1x/d RBV, 7 had nausea on 2x/d (5 improved on 1x/d), 5 hadvomiting on 2x/d (3 improved on 1x/d), 3 had diarrhea on 2x/d (one improved on 1x/d).None reported worse GI symptoms on 1x/d than on 2x/d dosing, despite taking the sameamount of RBV per day; most (8/9) preferred 1x/d dosing. For comparison, among 33patients on full-dose RBV 2x/d throughout treatment, 13 had nausea, 3 had vomiting, 10had diarrhea; 13/33 expressed a preference for 1x/d, 12 expressed a preference for 2x/d(primarily because this matched the drug label), and 8 had no preference. In a secondcomparison group, 6 patients took full-dose RBV 1x/d throughout, 2 had nausea, 2 hadvomiting, and 3 had diarrhea; all preferred 1x/d dosing. Nineteen people in a third comparisongroup started on full-dose RBV 2x/d and switched to 1x/d coincident with a 25-50% dosereduction; 11 had nausea on 2x/d (4 improved on 1x/d, with dose reduction); 3 had vomitingon 2x/d (1 improved on 1x/d, with dose reduction); 5 had diarrhea on 2x/d (2 improvedon 1x/d-dose, with reduction); 13/19 preferred 1x/d, one had no preference. Finally, amonga mixed group of 7 patients who had a dose reduction without a change in dosing schedule(one on 1x/d, 6 on 2x/d), 2 had nausea, none had vomiting, and 4 had diarrhea. CONCLU-SION: Once-daily use of RBV did not increase GI side effects compared to divided dosing,and most patients expressed a preference for 1x/d dosing. Our sample was small, however,with 35 people who took RBV 1x/d (in some cases at a reduced amount). Clinical managementwas complex. A randomized trial is needed to confirm our promising findings.

Sa1062

Characterization of anti-HCV Antibody Repertoire of IgG+ Memory B Cells inPatients With Chronic Hepatitis C and Spontaneous Resolvers in a SingleSource OutbreakAnne Olbrich, Thomas Berg, Hedda Wardemann, Julia Benckert

While in most cases acute hepatitis C virus (HCV) infection leads to the development ofchronic hepatitis C, spontaneous viral clearance occurs in a smaller percentage of individuals.For the successful control of the viral replication in the early phase of infection the adaptiveimmune system is crucial. Several studies have shown that protective anti-HCV antibodiesare able to prevent an infection with HCV. However, it is unknown whether differences inantibody repertoire mediate the ability to spontaneously eradicate the infection. The persis-tence of antibodies years and even decades after spontaneous (or treatment-induced) eradica-tion of HCV infection indicates that humoral memory is maintained even in the absence ofviral antigen over long periods.We isolated HCV specific IgG+memory B cells fromperipheralblood of 3 patients with chronic hepatitis C and 3 patients with spontaneous viral clearancethat were infected in a single-source outbreak by an identical HCV-strain in the context ofa contaminated Rhesus prophylaxis in the years 1978/79 in East Germany. Presentation of

S-986AASLD Abstracts

the antigen specificity as B cell receptor on the cell surface was used to isolate single HCV-specific IgG+ memory B cells by Fluorescence Assisted Cell Sorting (FACS). We used a RT-PCR based approach to clone and in vitro monoclonally express antibodies from singlememory B cells obtained from patients with spontaneous viral clearance and from chronicallyinfected individuals. By characterizing the individual heavy and light chain sequences ofeach cell we could show higher numbers of somatic hypermutation as sign of affinitymaturation as well as a biased repertoire of V-gene usage in heavy chains of patients withspontaneous viral clearance. The characterisation of the antibody reactivity profile of IgG+memory B cells of spontaneous resolvers and patients with chronic hepatitis C will giveinsights to the selection of human anti-HCV antibodies and will offer the opportunity toidentify and amplify protective antibodies against HCV. Human anti-HCV antibodies willhelp understanding humoral responses to viral antigens and may as well serve as a potentialtherapeutic option in infection prophylaxis by passive immunisation.

Sa1063

Hematological Indices Improve With Eradication of HCV in Cirrhosis andPredict Clinical Decompensation in Non RespondersRaffi Karagozian, Norman D. Grace, Amir A. Qamar

Background: The prevalence of anemia, thrombocytopenia, and leukopenia (alone or incombination) is relatively high in patients with cirrhosis from HCV. Abnormal hematologicalindices (HI) occur in HCV cirrhosis due to a number of causes including portal hypertension,low thrombopoietin levels and bone marrow suppression. Aims: To assess if HI improvewith HCV eradication and whether post treatment HI can predict clinical decompensationin patients who do not respond to treatment. Methods: A total of 153 patients with HCVcirrhosis treated with Peg-interferon and Ribavirin were identified. Inclusion criteria: .18years, therapy with Peginterferon and Ribavirin, compensated liver disease and Metavir scoreof 4 on biopsy. Exclusion criteria: early stage fibrosis, post-liver transplant, HIV co-infection,untreated patients. Abnormal HI was defined as Thrombocytopenia (TH) , 150,000, Leuko-penia (LE) , 4,000 and Anemia , 13.5 g/dl (male) 11.5 g/dl (female). Patients whodecompensated on therapy or with missing data points on follow-up were excluded. Clinicaland laboratory data were collected throughout follow-up. Repeated 2-way ANOVA wasperformed to compare means. Clinical decompensation (CD) was defined by new ascites,jaundice, encephalopathy or variceal hemorrhage during follow-up. Univariate and multivari-ate analysis was used to assess clinical decompensation. Results: A total of 131 patients metcriteria. The SVR rate was 26%. During a median follow-up of 56.5 months, PLT and WBCcounts improved in patients with HCV eradication compared to those where treatment wasunsuccessful (p,0.05) (FIGURE). On univariate analysis, the presence of TH (OR 15.6, p-value , 0.001) 6 months after completing therapy was significantly associated with CDwhile LE (OR 2.6, p-value 0.06) and anemia (OR 2.28, p-value 0.09) were not. Multivariateanalysis of variables at 6 months after completion of therapy continued to show TH (15.1,p-value , 0.001) predicted CD when controlled for albumin (OR 0.5, p-value 0.27), MELD(OR 1.1, p-value 0.63) and age (OR 0.98, p-value 0.54. Conclusion: PLT and WBC countsimprove significantly in patients with cirrhosis who respond to antiviral therapy againstHCV. The presence of thrombocytopenia 6 months after completion of antiviral therapypredicts a higher risk of clinical decompensation. After anti viral therapy, thrombocytopeniamay be considered as a predictor of poor prognosis in compensated cirrhosis after unsuccess-ful therapy.

Figure 1: Long term follow-up of platelets, leukocytes and hemoglobin post therapy. SVRpatients show significant improvement in platelets and leukocytes compared to non-SVRpatients in follow-up (p,0.05) while no difference in hemoglobin between SVR and Non-SVR groups was observed (p=0.96).