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898 Infections During Peginterferon (pegIFN)/Ribavirin (RBV) Therapy Are Associated With a Decline in Lymphocyte Count: Results of the IDEAL Study Michael Melia, Norbert Brau, Fred Poordad, Eric J. Lawitz, Mitchell L. Shiffman, John McHutchison, Andrew J. Muir, Greg Galler, Jonathan McCone, Lisa M. Nyberg, William M. Lee, Reem H. Ghalib, Eugene R. Schiff, Jianmin Long, Stephanie Noviello, Clifford A. Brass, Lisa D. Pedicone, Janice K. Albrecht, Mark Sulkowski Background: Bone marrow suppression due to PegIFN is a frequent adverse event during hepatitis C virus (HCV) treatment. However, the relationship between increased risk of infection and decreases in white blood cell lines is unclear. The objective of this analysis was to determine the incidence and risk factors for infections during PegIFN/RBV therapy. Methods: 3070 treatment-naive, HCV genotype 1-infected patients were treated for up to 48 weeks with PegIFN-2b 1.5 or 1 μg/kg/week plus RBV 800-1400 mg/day, or PegIFN-2a 180 μg/week plus RBV 1000-1200 mg/day. White blood cell counts with differential were obtained every 4-6 weeks while on-treatment. Per protocol, dose reduction was required for neutrophils <0.75 × 10 9 /L, and treatment discontinuation was required for neutrophils <0.5 × 10 9 /L. G-CSF was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. Results: While on treatment, 1092 (36%) patients experienced an adverse event classified as an infection (any severity), and 581 (19%) patients experienced moderate to life-threatening infections. For 3042 patients with at least one available on-treatment neutrophil and lymphocyte count, the mean max- imum declines in neutrophil and lymphocyte counts from baseline during treatment were 2.5 × 10 9 /L and 1.3 × 10 9 /L with mean minimum values between 1.2 × 10 9 /L and 0.9 × 10 9 /L, respectively. During treatment, 648 (21%) patients had at least one neutrophil count <0.75 × 10 9 /L, but only 242 (8%) patients had an infection (any severity) and neutrophils <0.75 × 10 9 /L any time while on treatment. There were 12 patients with severe or life- threatening infection and neutrophil count <0.75 × 10 9 /L, but only 4 patients had temporally related infections (defined as neutrophil count <0.75 × 10 9 /L within 60 days prior to the onset of infection). Of these 4 patients, only 1 event (sepsis) was considered related to PegIFN/RBV treatment. In a multivariate logistic regression model using stepwise selection method with baseline demographic/disease characteristics and on-treatment minimum hema- tologic parameters, minimum on-treatment lymphocyte count and female gender were the only predictors of moderate to life-threatening infection (Figure). Conclusions: In the IDEAL study, although neutropenia was common, decline in lymphocyte count and female gender were the only factors independently associated with moderate to life-threatening infection. Further research is needed to understand this relationship. 899 Response-Guided Therapy as an Effective Strategy on Peginterferon Alpha-2B Plus Ribavirin for Chronic Hepatitis C With Genotype 2 and a High Viral Road Ken Sato, Hiroaki Hashizume, Yuichi Yamazaki, Norio Horiguchi, Satoru Kakizaki, Hitoshi Takagi, Masatomo Mori Background: The sustained virological response (SVR) rate in patients infected with hepatitis C virus (HCV) is reported to be closely associated with rapid virological response (RVR; HCV RNA level <50 IU/mL at week 4) of therapy with peginterferon alfa-2b plus ribavirin. Patients infected with HCV genotype 2 and a high viral road have SVR rates of approximately 70-80% after 24-week peginterferon plus ribavirin therapy. Aim: We conducted a prospective study to optimize the therapy duration of peginterferon alfa-2b plus ribavirin therapy based on virological response at week 2 and 4 after receiving therapy. Patients and Methods: A total 146 study subjects with HCV genotype 2 and a high viral road have received peginter- feron alfa-2b 1.5μg/kg/week plus ribavirin based on body weight daily. The therapy duration was assigned to be 12 weeks in patients achieving super rapid virological response (SRVR; HCV RNA level <50 IU/mL at week 2), 24 weeks in patients achieving RVR, and 48 weeks in patients showing late virological response (LVR; HCV RNA level50IU/mL at week 4). A SVR was defined as an undetectable serum HCV RNA level (<50 IU/mL) 24 weeks after the end of therapy. Results: The overall SVR rate was 76.7% (112/146) comparable to the established reports. The SVR rate was 91.7% (11/12), 92.8% (64/69), and 72.2% (13/18) in SRVR group, RVR group, and LVR group, respectively. The patients that did not agree with the study protocol and showed LVR revealed only 51.1% (24/47) of the SVR rate for 24-week therapy. Although there was no significant difference of the SVR rate in patients with LVR between 24-week therapy and 48-week therapy, 48-week therapy had a tendency to increase the SVR rate in patients with LVR (p=0.17). Furthermore, 24-week therapy achieved significant high rate of SVR in patients with RVR than those with LVR (p<0.0001). Predictive factors of SVR in 24-week therapy were found to be achievement of RVR, history of conventional interferon therapy, and viral genotype (2a or 2b) by multiple logistic regression analysis. Although the rates of dose reduction of ribavirin and adverse events including decrease of the platelet counts had a tendency to increase as the dosing period increased, S-911 AASLD Abstracts 48-week therapy was overall well-tolerated. Conclusions: The SVR rate for 12-week therapy in SRVR group or 24-week therapy in RVR group was promising and this strategy was very useful for optimizing the therapy duration. In LVR group, however, even 48-week therapy was unsatisfactory in view of the SVR rate. Thus, response-guided therapy in LVR group needs to be much improved. 900 Substance-Associated Co-Morbidity During Oral Maintenance Therapy Impacts Outcome of Hepatitis C Therapy: Conjoint Analysis of Data From Two German Noninterventional Cohorts Bernd Weber, Stefan Mauss, Karl-Heinz Hey, Waizmann Michael, Andreas Schober, Gabriele Bellmann, Karl-Georg Büscher, Ralph Link, Sabine Mauruschat, Konrad F. Cimander, Antje Breske, Stephan Walcher Background: There is still reluctance treating patients under opioid maintenance therapy for chronic hepatitis C with concomitant drug abuse being the main concern. Little is known, however, about the effect of concomitant drug abuse on outcome of HCV-therapy under real-life conditions. Methods: From October 2005 to August 2010, 1630 patients with chronic HCV who were on stable opioid maintenance due to illicit drug abuse were documented in the non-interventional study PRISMA and the ongoing German-wide observational study on chronic hepatitis C therapy (bng/Roche). In the current analysis, patients were stratified according to concomitant use of illicit drugs, none, 1-3 illicit drugs or 4 substances. The SVR was assessed according to the intensity of illicit drug use . Results: This analysis includes 767 patients completing a period corresponding to the standard duration of HCV-therapy plus 24 weeks follow-up. Main baseline-characteristics: age 35.9 ± 9.3 years, 76.3 % male, BMI 24.2 ± 3.7 kg/m2, mean known duration of infection 8.9 ± 6.4 years, GT-1/4 48.6%, GT-2/3 51.4%, 58.7% high HCV-RNA (400.000 IU/ml). Mean duration of therapy in GT 1/4 36.7±17.4 weeks and 23.4± 9.3 weeks in GT 2/3. Opioid maintenance therapy: 54.6% methadone (mean daily dose 57.4 mg), 24.5% L-polamidone (mean 40.4 mg), 16.7% buprenorphine (mean 8. 7 mg), 1.3% other. Concomitant illicit drug use during HCV- therapy: cocaine (4.7%), opiates (7.8%), benzodiazepines (8.3%), amphetamines (1.2%), cannabis (26.1%). Overall, SVR was observed in 49.9% pts. (43.4% GT-1/4 vs. 56.1% GT- 2/3). SVR was observed in 54.1% pts. with concomitant use of illicit drugs and in 37.9% pts. without (p < 0.0001). SVR was not lower in pts. with concomitant use of 4 illicit drugs compared to concomitant use of 1-3 substances (76.5% vs. 53.4%; p = 0.082). Treatment discontinuation: no illicit drug use 39.9 %, concomitant use of 1-3 substances 24.6%, 4 substances 17,6%. Conclusion: These data demonstrate that patients on stable opioid maintenance with concomitant illicit drug use and even polysubstance abuse can be successfully treated with Peg-IFN and ribavirin due to good adherence to therapy. Thus, multiple concomitant illicit drug use is not per se an exclusion criterion for hepatitis C therapy. 901 Interferon Alfa Antibody (IFN Alfa Ab) as a Useful Predictive Marker of Sustained Viral Response (SVR) for Therapy in Chronic Hepatitis C P Patrick Basu, Nithya Krishnaswamy, Niraj James Shah, Sajith J. Foustin, Chris Tang, Robert S. Brown Purpose: Interferon alfa is the mainstay of therapy for hepatitis C infection. Sustained viral response (SVR) remains 46% in all genotypes. On treatment, rapid viral response (RVR) and early viral response (EVR) are predictive markers of SVR and treatment modification. We propose a novel marker, IFN alfa Ab, in predicting response of interferon alfa therapy on chronic hepatitis C naïve genotype 1 patients. IL28b polymorphism proved to be important indicator of SVR. Methods: Forty (n=40) patients (age:45.2±7.2 years, mean±SD; range:26- 56 years) were recruited with hepatitis C genotype1 who underwent pegylated Interferon alfa 2a plus weight based ribavirin for 48weeks. Serum levels of IFN alfa Ab were obtained initially at 0 week, 2nd, 4th, 12th, 24th, 48th, and 72nd weeks respectively. Exclusion: Co- infection, hemolytic syndromes, severe cardiac disease, severe depression, uncontrolled diabetes mellitus, decompensated cirrhosis, and patients actively using illicit drugs and alcohol consumption >50 g per day. IL28b polymorphism was evaluated. Results: 25/40 (62.5%) achieved SVR. 31/40 (77.5%) developed IFN alfa Ab during the treatment (14/ 31(45%) at 12th week, 16/31(52%) at 24th week, and 1/31(3%) at 48th week0; 15/31(48.4%) had higher titers (1:150). 13/14 (92.9%) with Ab at 12th week had higher titers. The presence of high-titer Ab at 12th week predicted failure of SVR with 86.7% sensitivity, 100% specificity, 100% positive predictive value, with 92.6% negative predictive value. 11 Afro-Americans developed high-titer Ab at 12th week and failed SVR. 22/40 (55%) with high viral load >400k failed SVR. IL28b has no negative impact in IFN Ab. Conclusion: Majority of patients during interferon therapy developed IFN alfa Ab at some period. This study postulates that the early presence of high titer Ab at week 12 predicts the failure of SVR with high sensitivity and specificity. Afro-Americans developed high-titer Ab early and failed SVR. Ab titers do not correlate with BMI, age, sex, and fibrotic score but predict failure of SVR. There was no association of IL28b polymorphism with the development of IFN Ab. This study may modify the recent treatment paradigm with cost benefits. IFN Ab may be a prognostic tool for truncated Therapy. A larger prospective trial is needed. 902 Subanalyses of the Telaprevir Lead-in ARM in the Realize Study: Response at Week 4 is Not a Substitute for Prior Null Response Categorization Eric J. Lawitz, Graham Foster, Stefan Zeuzem, Paul Pockros, Zobair M. Younossi, Pietro Andreone, Stanislas Pol, Moises Diago, Stuart K. Roberts, Isabelle Lonjon-Domanec, Rolf van Heeswijk, Sandra De Meyer, Don Luo, Shelley George, Maria Beumont-Mauviel, Gaston Picchio Background and Aims: On treatment, a poor therapeutic response to peginterferon(P)/ ribavirin(R) is defined as a <1 log 10 decline in viral load at week 4. Null response (NR) to a current or prior course of PR is defined as a <2 log 10 decline in HCV RNA at week 12. AASLD Abstracts

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898

Infections During Peginterferon (pegIFN)/Ribavirin (RBV) Therapy AreAssociated With a Decline in Lymphocyte Count: Results of the IDEAL StudyMichael Melia, Norbert Brau, Fred Poordad, Eric J. Lawitz, Mitchell L. Shiffman, JohnMcHutchison, Andrew J. Muir, Greg Galler, Jonathan McCone, Lisa M. Nyberg, WilliamM. Lee, Reem H. Ghalib, Eugene R. Schiff, Jianmin Long, Stephanie Noviello, Clifford A.Brass, Lisa D. Pedicone, Janice K. Albrecht, Mark Sulkowski

Background: Bone marrow suppression due to PegIFN is a frequent adverse event duringhepatitis C virus (HCV) treatment. However, the relationship between increased risk ofinfection and decreases in white blood cell lines is unclear. The objective of this analysiswas to determine the incidence and risk factors for infections during PegIFN/RBV therapy.Methods: 3070 treatment-naive, HCV genotype 1-infected patients were treated for up to48 weeks with PegIFN-2b 1.5 or 1 μg/kg/week plus RBV 800-1400 mg/day, or PegIFN-2a180 μg/week plus RBV 1000-1200 mg/day. White blood cell counts with differential wereobtained every 4-6 weeks while on-treatment. Per protocol, dose reduction was requiredfor neutrophils <0.75 × 109/L, and treatment discontinuation was required for neutrophils<0.5 × 109/L. G-CSF was prohibited. Data on infections were captured at each study visitand categorized according to MedDRA version 13.0. Results: While on treatment, 1092(36%) patients experienced an adverse event classified as an infection (any severity), and581 (19%) patients experienced moderate to life-threatening infections. For 3042 patientswith at least one available on-treatment neutrophil and lymphocyte count, the mean max-imum declines in neutrophil and lymphocyte counts from baseline during treatment were2.5 × 109/L and 1.3 × 109/L with mean minimum values between 1.2 × 109/L and 0.9 ×109/L, respectively. During treatment, 648 (21%) patients had at least one neutrophil count<0.75 × 109/L, but only 242 (8%) patients had an infection (any severity) and neutrophils<0.75 × 109/L any time while on treatment. There were 12 patients with severe or life-threatening infection and neutrophil count <0.75 × 109/L, but only 4 patients had temporallyrelated infections (defined as neutrophil count <0.75 × 109/L within 60 days prior to theonset of infection). Of these 4 patients, only 1 event (sepsis) was considered related toPegIFN/RBV treatment. In a multivariate logistic regression model using stepwise selectionmethod with baseline demographic/disease characteristics and on-treatment minimum hema-tologic parameters, minimum on-treatment lymphocyte count and female gender were theonly predictors of moderate to life-threatening infection (Figure).Conclusions: In the IDEALstudy, although neutropenia was common, decline in lymphocyte count and female genderwere the only factors independently associated with moderate to life-threatening infection.Further research is needed to understand this relationship.

899

Response-Guided Therapy as an Effective Strategy on Peginterferon Alpha-2BPlus Ribavirin for Chronic Hepatitis C With Genotype 2 and a High ViralRoadKen Sato, Hiroaki Hashizume, Yuichi Yamazaki, Norio Horiguchi, Satoru Kakizaki,Hitoshi Takagi, Masatomo Mori

Background: The sustained virological response (SVR) rate in patients infected with hepatitisC virus (HCV) is reported to be closely associated with rapid virological response (RVR;HCV RNA level <50 IU/mL at week 4) of therapy with peginterferon alfa-2b plus ribavirin.Patients infected with HCV genotype 2 and a high viral road have SVR rates of approximately70-80% after 24-week peginterferon plus ribavirin therapy. Aim:We conducted a prospectivestudy to optimize the therapy duration of peginterferon alfa-2b plus ribavirin therapy basedon virological response at week 2 and 4 after receiving therapy. Patients and Methods: Atotal 146 study subjects with HCV genotype 2 and a high viral road have received peginter-feron alfa-2b 1.5μg/kg/week plus ribavirin based on body weight daily. The therapy durationwas assigned to be 12 weeks in patients achieving super rapid virological response (SRVR;HCV RNA level <50 IU/mL at week 2), 24 weeks in patients achieving RVR, and 48 weeksin patients showing late virological response (LVR; HCV RNA level≧50IU/mL at week 4).A SVR was defined as an undetectable serum HCV RNA level (<50 IU/mL) 24 weeks afterthe end of therapy. Results: The overall SVR rate was 76.7% (112/146) comparable to theestablished reports. The SVR rate was 91.7% (11/12), 92.8% (64/69), and 72.2% (13/18)in SRVR group, RVR group, and LVR group, respectively. The patients that did not agreewith the study protocol and showed LVR revealed only 51.1% (24/47) of the SVR rate for24-week therapy. Although there was no significant difference of the SVR rate in patientswith LVR between 24-week therapy and 48-week therapy, 48-week therapy had a tendencyto increase the SVR rate in patients with LVR (p=0.17). Furthermore, 24-week therapyachieved significant high rate of SVR in patients with RVR than those with LVR (p<0.0001).Predictive factors of SVR in 24-week therapy were found to be achievement of RVR, history ofconventional interferon therapy, and viral genotype (2a or 2b) by multiple logistic regressionanalysis. Although the rates of dose reduction of ribavirin and adverse events includingdecrease of the platelet counts had a tendency to increase as the dosing period increased,

S-911 AASLD Abstracts

48-week therapy was overall well-tolerated. Conclusions: The SVR rate for 12-week therapyin SRVR group or 24-week therapy in RVR group was promising and this strategy was veryuseful for optimizing the therapy duration. In LVR group, however, even 48-week therapywas unsatisfactory in view of the SVR rate. Thus, response-guided therapy in LVR groupneeds to be much improved.

900

Substance-Associated Co-Morbidity During Oral Maintenance Therapy ImpactsOutcome of Hepatitis C Therapy: Conjoint Analysis of Data From TwoGerman Noninterventional CohortsBernd Weber, Stefan Mauss, Karl-Heinz Hey, Waizmann Michael, Andreas Schober,Gabriele Bellmann, Karl-Georg Büscher, Ralph Link, Sabine Mauruschat, Konrad F.Cimander, Antje Breske, Stephan Walcher

Background: There is still reluctance treating patients under opioid maintenance therapyfor chronic hepatitis C with concomitant drug abuse being the main concern. Little is known,however, about the effect of concomitant drug abuse on outcome of HCV-therapy underreal-life conditions. Methods: FromOctober 2005 to August 2010, 1630 patients with chronicHCV who were on stable opioid maintenance due to illicit drug abuse were documented inthe non-interventional study PRISMA and the ongoing German-wide observational studyon chronic hepatitis C therapy (bng/Roche). In the current analysis, patients were stratifiedaccording to concomitant use of illicit drugs, none, 1-3 illicit drugs or ≥4 substances. TheSVR was assessed according to the intensity of illicit drug use . Results: This analysis includes767 patients completing a period corresponding to the standard duration of HCV-therapyplus 24 weeks follow-up. Main baseline-characteristics: age 35.9 ± 9.3 years, 76.3 % male,BMI 24.2 ± 3.7 kg/m2, mean known duration of infection 8.9 ± 6.4 years, GT-1/4 48.6%,GT-2/3 51.4%, 58.7% high HCV-RNA (≥400.000 IU/ml). Mean duration of therapy in GT1/4 36.7±17.4 weeks and 23.4± 9.3 weeks in GT 2/3. Opioid maintenance therapy: 54.6%methadone (mean daily dose 57.4 mg), 24.5% L-polamidone (mean 40.4 mg), 16.7%buprenorphine (mean 8. 7 mg), 1.3% other. Concomitant illicit drug use during HCV-therapy: cocaine (4.7%), opiates (7.8%), benzodiazepines (8.3%), amphetamines (1.2%),cannabis (26.1%). Overall, SVR was observed in 49.9% pts. (43.4% GT-1/4 vs. 56.1% GT-2/3). SVR was observed in 54.1% pts. with concomitant use of illicit drugs and in 37.9%pts. without (p < 0.0001). SVR was not lower in pts. with concomitant use of ≥4 illicitdrugs compared to concomitant use of 1-3 substances (76.5% vs. 53.4%; p = 0.082).Treatment discontinuation: no illicit drug use 39.9 %, concomitant use of 1-3 substances24.6%, ≥4 substances 17,6%. Conclusion: These data demonstrate that patients on stableopioid maintenance with concomitant illicit drug use and even polysubstance abuse can besuccessfully treated with Peg-IFN and ribavirin due to good adherence to therapy. Thus,multiple concomitant illicit drug use is not per se an exclusion criterion for hepatitis C therapy.

901

Interferon Alfa Antibody (IFN Alfa Ab) as a Useful Predictive Marker ofSustained Viral Response (SVR) for Therapy in Chronic Hepatitis CP Patrick Basu, Nithya Krishnaswamy, Niraj James Shah, Sajith J. Foustin, Chris Tang,Robert S. Brown

Purpose: Interferon alfa is the mainstay of therapy for hepatitis C infection. Sustained viralresponse (SVR) remains 46% in all genotypes. On treatment, rapid viral response (RVR)and early viral response (EVR) are predictive markers of SVR and treatment modification.We propose a novel marker, IFN alfa Ab, in predicting response of interferon alfa therapyon chronic hepatitis C naïve genotype 1 patients. IL28b polymorphism proved to be importantindicator of SVR. Methods: Forty (n=40) patients (age:45.2±7.2 years, mean±SD; range:26-56 years) were recruited with hepatitis C genotype1 who underwent pegylated Interferonalfa 2a plus weight based ribavirin for 48weeks. Serum levels of IFN alfa Ab were obtainedinitially at 0 week, 2nd, 4th, 12th, 24th, 48th, and 72nd weeks respectively. Exclusion: Co-infection, hemolytic syndromes, severe cardiac disease, severe depression, uncontrolleddiabetes mellitus, decompensated cirrhosis, and patients actively using illicit drugs andalcohol consumption >50 g per day. IL28b polymorphism was evaluated. Results: 25/40(62.5%) achieved SVR. 31/40 (77.5%) developed IFN alfa Ab during the treatment (14/31(45%) at 12thweek, 16/31(52%) at 24th week, and 1/31(3%) at 48th week0; 15/31(48.4%)had higher titers (≥1:150). 13/14 (92.9%) with Ab at 12th week had higher titers. Thepresence of high-titer Ab at 12th week predicted failure of SVR with 86.7% sensitivity,100% specificity, 100% positive predictive value, with 92.6% negative predictive value. 11Afro-Americans developed high-titer Ab at 12th week and failed SVR. 22/40 (55%) withhigh viral load >400k failed SVR. IL28b has no negative impact in IFN Ab. Conclusion:Majority of patients during interferon therapy developed IFN alfa Ab at some period. Thisstudy postulates that the early presence of high titer Ab at week 12 predicts the failure ofSVR with high sensitivity and specificity. Afro-Americans developed high-titer Ab early andfailed SVR. Ab titers do not correlate with BMI, age, sex, and fibrotic score but predictfailure of SVR. There was no association of IL28b polymorphism with the development ofIFN Ab. This study may modify the recent treatment paradigm with cost benefits. IFN Abmay be a prognostic tool for truncated Therapy. A larger prospective trial is needed.

902

Subanalyses of the Telaprevir Lead-in ARM in the Realize Study: Response atWeek 4 is Not a Substitute for Prior Null Response CategorizationEric J. Lawitz, Graham Foster, Stefan Zeuzem, Paul Pockros, Zobair M. Younossi, PietroAndreone, Stanislas Pol, Moises Diago, Stuart K. Roberts, Isabelle Lonjon-Domanec, Rolfvan Heeswijk, Sandra De Meyer, Don Luo, Shelley George, Maria Beumont-Mauviel,Gaston Picchio

Background and Aims: On treatment, a poor therapeutic response to peginterferon(P)/ribavirin(R) is defined as a <1 log10 decline in viral load at week 4. Null response (NR) toa current or prior course of PR is defined as a <2 log10 decline in HCV RNA at week 12.

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