End Of Treatment Response Rate Research Articles

Efficacy and safety of ledipasvir/sofosbuvir in 5,028 Mongolian patients infected with genotype 1 hepatitis C virus: A multicenter study.

Background/AimsLedipasvir/sofosbuvir (LDV/SOF) shows high efficacy and safety in patients with genotype 1-hepatitis C virus (HCV). We aimed to investigate the efficacy and safety of LDV/SOF in real-world Mongolian patients.MethodsBetween 2015 to 2019, 23 (0.5%) and 5,005 patients (99.5%) with genotype 1a and 1b HCV, respectively, were treated with a fixed-dose tablet containing 90 mg ledipasvir and 400 mg sofosbuvir for 12 weeks, and 81 patients (1.6%) with previous experience of interferon (IFN)-based treatment received additional 1,000 mg ribavirin. HCV RNA was measured at 4, 12, and 24 weeks after the first dose to determine rapid virologic response, end of treatment response (ETR), and sustained virologic response at 12 weeks after end of treatment (SVR12).ResultsMost patients (n=5,008; 99.6%) achieved ETR and SVR12 without virologic relapse. Patients with genotype 1a showed low rates of ETR and SVR12 in only 16 patients (69.6%). There was no significant difference in SVR12 rate between patients regardless of IFN experience (n=81; 1.6%), cirrhosis (n=1,151; 22.9%), HCV RNA >6×106 IU/mL (n=866; 17.2%), or liver stiffness >9.6 kPa (n=1,721; 34.2%) (100.0%, 99.3%, 99.4%, and 99.4%, respectively). No severe adverse events (AEs) were reported, and there was no dose reduction or interruption due to AE. The most common AEs were headache (n=472; 9.4%), fatigue (n=306; 6.2%), abdominal discomfort (n=295; 5.9%), and skin rash (n=141; 2.8%).ConclusionsLDV/SOF showed high efficacy and safety for patients with genotype 1, especially 1b HCV, in Mongolia. The real-world data might be applicable to patients in other Asian-Pacific countries.

Efficacy and safety of daclatasvir-containing regimens in the treatment of chronic hepatitis C patients in Damietta

Background Chronic hepatitis C virus infection is one of the most important health problems in Egypt. Since November 2015, generic sofosbuvir (SOF) with daclatasvir (DCV)±ribavirin (RBV) became the standard treatment in all National Committee for Control of Viral Hepatitis centers. Yet, the long-term efficacy, safety, and late complications of generic direct-acting antiviral drugs have not been studied. Aims Evaluation of the efficacy and safety of generic DCV-containing regimens in the treatment of chronic hepatitis C patients after 72 weeks of close follow-up. Patients and methods A total of 150 chronic hepatitis C virus patients were classified into easy-to-treat group (naive patients with no evidence of cirrhosis) and difficult-to-treat group (treatment experienced or have any evidence of cirrhosis) and treated for 12 weeks with generic medications: DCV 60 mg and SOF 400 mg±RBV in easy and difficult-to-treat groups, respectively. A close follow-up of up to 72 weeks was done to assess the efficacy and safety of the generic drugs. Results Overall sustained virologic response (SVR12) was 94.0%, while the end of treatment response rate was 94.7%. SVR12 rates in easy-to-treat and difficult-to-treat groups were 97.06 and 91.46%, respectively. Multivariate analysis revealed that absence of cirrhosis, higher baseline albumin, lower baseline international normalized ratio, higher baseline platelet count, lower baseline alpha-fetoprotein, normal splenic size, and naivety to previous antiviral therapy were associated with SVR12. PCR after 72 weeks for those who achieve SVR12 is still undetectable. Three cases died during the follow-up period and were related to their advanced liver disease. No serious adverse events were reported. Conclusion Generic DCV, SOF±RBV regimen is safe and effective for treatment of chronic hepatitis C with minimal adverse events and SVR12 is efficient to predict persistent viral clearance.

Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.

10013 Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 < 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&scIL2. Patients with evaluable disease prior DB or DB&scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&4 toxicity was lower in the group with DB vs DB&scIL2 for fever (14%vs31%, p < 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate > 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.

The predictors of sustained virological response with sofosbuvir and ribavirin in patients with chronic hepatitis C genotype 2.

Background/AimsReal-world, clinical practice data are lacking about sofosbuvir/ribavirin (SOF/RBV) treatment of Korean patients with hepatitis C virus genotype 2 (HCV GT2) infection. This study investigated the efficacy and safety of SOF/RBV in Korean patients with HCV GT2 infection and clinical factors predicting sustained virological response 12 weeks (SVR12) after the end of SOF/RBV treatment.MethodsA total of 181 patients with HCV GT2 with/without cirrhosis were treated with SOF/RBV for 16/12 weeks. Rapid virological response (RVR) was defined as non-detectable HCV RNA at 4 weeks.ResultsThe RVR rate was 80.7% (146/181), the end of treatment response rate was 97.8% (177/181) and the SVR12 rate was 92.8% (168/181). Of eight patients with relapse, four did not achieve RVR. Three patients had a history of hepatocellular carcinoma (HCC). Multivariable analysis showed that RVR (p = 0.015) and no previous history of HCC (p = 0.007) were associated with SVR12. Factors significantly contributing to RVR included cirrhosis, creatinine concentration, and pre-treatment HCV RNA level. SVR12 rate was significantly higher in RVR (+) than RVR (–) patients (95.2% vs. 82.9%, p = 0.011) and also significantly higher in patients without than with a history of HCC (94.1% vs. 72.7%, p = 0.008). During treatment, 80/181 patients (44.2%) experienced mild to moderate adverse events, with 32 (17.7%) requiring RBV dose reductions due to anemia.ConclusionsSOF/RBV treatment was effective and tolerable in HCV GT2 patients. RVR and no previous history of HCC were positive predictors of SVR12.

Daclatasvir and asunaprevir combination therapy for patients with chronic hepatitis C virus genotype 1b infection in real world.

Background/AimsPrevious studies have reported a high rate of sustained virologic response (SVR) and a low rate of serious adverse events with the use of daclatasvir (DCV) and asunaprevir (ASV) combination therapy. We evaluated the efficacy and safety of DCV and ASV combination therapy for patients with chronic hepatitis C virus (HCV) genotype 1b infection in real world.MethodsWe enrolled 278 patients (184 treatment-naïve patients) from five hospitals in Daegu and Gyeongsangbuk-do. We evaluated the rates of rapid virologic response (RVR), end-of-treatment response (ETR), and SVR at 12 weeks after completion of treatment (SVR12). Furthermore, we investigated the rate of adverse events and predictive factors of SVR12 failure.ResultsThe mean age of patients was 59.5 ± 10.6 years, and 140 patients (50.2%) were men. Seventy-seven patients had cirrhosis. Baseline information regarding nonstructural protein 5A (NS5A) sequences was available in 268 patients. Six patients presented with pretreatment NS5A resistance-associated variants. The RVR and the ETR rates were 96.6% (258/267) and 95.2% (223/232), respectively. The overall SVR12 rate was 91.6% (197/215). Adverse events occurred in 17 patients (7.9%). Six patients discontinued treatment because of liver enzyme elevation (n = 4) and severe nausea (n = 2). Among these, four achieved SVR12. Other adverse events observed were fatigue, headache, diarrhea, dizziness, loss of appetite, skin rash, and dyspnea. Univariate analysis did not show significant predictive factors of SVR12 failure.ConclusionsDCV and ASV combination therapy showed high rates of RVR, ETR, and SVR12 in chronic HCV genotype 1b-infected patients in real world and was well tolerated without serious adverse events.

Comparative Study between Triple Therapy (Peginterferon /Ribavirin/Sofosbuvir) and Dual Therapy (Simeprevir /Sofosbuvir) in Treatment of Chronic HCV Patients

Background and study aim: Major changes have emerged during the last few years in the treatment of chronic HCV infection. Several direct acting antiviral agents (DAAs) have been developed showing potent activity with higher rates of sustained virological response. This study shows comparison between triple therapy regimen (Peginterferon/ Ribavirin/ Sofosbuvir) and dual therapy regimen (Simprevir/Sofosbuvir) concerning efficacy and safety for Egyptian patients with chronic HCV infection. Patients and Methods: This retrospective comparative study included 500 Egyptian patients with chronic HCV infection, randomly selected from Beni-Suef centre of treatment of viral hepatitis affiliated to the National committee for control of viral hepatitis (NCCVH). They were classified into two groups; triple therapy group included 250 patients had received pegylated interferon alpha, ribavirin and sofosbuvir for 12 weeks and dual therapy group included 250 patients had received sofosbuvir and simeprevir for 12 weeks. All patients were monitored for treatment safety and efficacy. Results: In the triple therapy group, mostly observed clinical side effects were; flu like illness (40% of patients), GI manifestations (20.8% of patients) and psychological manifestations (10.4% of patients) while photosensitivity (22% of patients), flu like illness (18.8% of patients) and GI manifestations (4.8% of patients) were the most frequently occurring clinical adverse effects in dual therapy group. Anemia (62.4% of patients) and leucopenia (49.6% of patients) were the mostly observed hematological abnormalities in triple therapy group while hyperbilirubinemia (38% of patients) was the mainly observed biochemical abnormality in dual therapy group. In the triple therapy group, the end of treatment response (ETR) rate was 95.6% while sustained virological response (SVR) rate was 91.2%. In dual therapy group, ETR rate was 95.6 % while SVR rate was 93.6 %. Conclusion: The dual therapy (Simeprevir and Sofosbuvir) regimen is more tolerated than triple therapy (Peginterferon, Ribavirin and Sofosbuvir) regimen for Egyptian patients with chronic HCV infection. There was no statistically significant difference as regard sustained virological response between both triple therapy and dual therapy regimens.

The Impact of Interleukin-28B rs12979860 Polymorphism on Peginterferon-alpha and Ribavirin Combination Therapy in Iranian Patients with Hepatitis C Virus Genotype 1 Infection

Background: Hepatitis C virus (HCV) infection is a global health problem. Most cases of HCV infection do not resolve spontaneously. Combination therapy with pegylated interferon-α (PegIFN-alpha) and ribavirin (RBV) is the standard treatment for patients with HCV infection. The success of treatment is affected by several host, viral, and treatment factors. Available works have demonstrated significant role of interleukin 28B (IL28B) polymorphisms in predicting HCV infection treatment outcomes. This suggests the possibility of tailored therapy in HCV infected patients. HCV is one of the most common causes of liver disease worldwide. If untreated, this infection can develop chronic hepatitis in 50%-85% of patients. The aim of current study is to determine the association of interleukin-28B (IL-28B) rs-12979860 polymorphism in response to peginterferon-alpha (PegIFN-alpha) and ribavirin combination therapy in Iranian patients with chronic hepatitis C genotype 1 infection. Methods: This cross-sectional study was carried out on 70 Iranian patients with chronic hepatitis C infection (genotype 1) receiving PegIFN-alpha and ribavirin. DNA was extracted from blood samples. Specific primers were used to amplify targeted polymorphisms. Results: In this study, 71.4% of patients reached sustained virological response (SVR). The prevalence of CC, CT and TT genotypes were 38.6%, 42.8% and 18.6% respectively. The rate of SVR was 96.3 for CC genotype, whereas this rate was 66.7 for CT and 30.8 for TT genotypes. We found an association between end of treatment response (ETR) and IL-28B genotypes as 100% of patients bearing CC genotype reached ETR, but ETR rate was 45.85% in CT group and 10.2% in TT group. Six months follow-up showed that there was a significant difference between response to treatment in patients IL-28B-CC and TT (P < 0.001). Data regression analysis showed that CC genotype was an independent predicting factor, significantly associated with higher SVR (P = 0.005 (OR=36.1; 95% CI = 3 - 434.2)). In contrast, absence of C allele (TT genotype) was significantly correlated with the failure of response (P = 0.005 (OR = 36.1; 95% CI = 3 - 434.2)). Conclusions: The results showed that IL-28B rs12979860 was an important predictor of HCV treatment response.

Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients.

Major changes have emerged during the last few years in the therapy of chronic HCV. Several direct acting antiviral agents have been developed showing potent activity with higher rates of sustained virological response, even in difficult-to-treat patients. This study explores real life experience concerning efficacy, safety and possible predictors of response for the first cohort of Egyptian patients with chronic HCV genotype IV treated with Sofosbuvir/Simprevir combination therapy. This real life study recruited the first (6211) chronic HCV genotype IV Egyptian patients, who received antiviral therapy in viral hepatitis specialized treatment centres affiliated to the National committee for control of viral hepatitis. All enrolled patients received 12weeks course of daily combination of sofosbuvir (400mg) and simeprevir (150mg). Patients were closely monitored for treatment safety and efficacy. Overall sustained virological response 12 rate was 94.0% while the end of treatment response rate was 97.6%. sustained virological response 12 rates in easy and difficult-to-treat groups were 96% and 93% respectively. Univariate and multivariate logistic regression analysis revealed significant association of low albumin (<3.5), cirrhosis and Fib-4 score (>3.25) with treatment failure. Fatal adverse events occurred in 23/6211 cases (0.37%) due to liver cell failure adverse events or SAEs leading to treatment discontinuation occurred in 97 patients (1.6%). Sofosbuvir/Simeprevir combination is an effective and well tolerated regimen for patients with chronic HCV genotype IV.

Pegylated Interferon/Ribavirin dual therapy in patients with chronic Hepatitis C: results of 323 cases

Objective: The combination of pegylated interferon-α (PEG-IFN) and ribavirin has become a mainstay in the treatment of chronic hepatitis C (CHC). We aimed to evaluate the efficacy of this treatment in patients with CHC, while considering new approaches. Methods: A total of 323 patients with CHC underwent PEG-IFN and ribavirin combination treatment from the 3 centers (2 in Ordu and 1 in Samsun provinces) in Middle Black Sea region between the years of 2003-2013. Results: Of the patients, 208 (67%) were female and had a mean age 54 ± 10 years (median: 54; 19-70). Genotyping was performed in 163 patients, and 161 patients (98.8%) revealed genotype 1. Sustained virologic response (SVR) and the end of treatment response rates ere 58.3% and 75.6%, respectively. In patients with rapid virological response, the SVR rate was 85.1%, whereas in patients with a HCV RNA level less than 800,000 IU/ml, the SVR rate was 71.2%. The SVR rates were found to be higher in patients who developed hypothyroidism, which was statistically significant (p = 0.03). The most frequent side effect was anemia, followed by thrombocytopenia, fatigue, and loss of appetite. Conclusion: Presently, PEG-IFN/ribavirin is still an option in the treatment of certain patient populations even after the consideration of newer treatment methods. J Microbiol Infect Dis 2015;5(4): 151-155 Key words: Pegylated interferon, ribavirin, therapy, hepatitis C

Triple Therapy Using Direct-Acting Agents for Recurrent Hepatitis C After Liver Transplantation: A Single-Center Experience

BackgroundHepatitis C viral graft reinfection is almost a universal event after liver transplantation with consequent disease progression. MethodsWe applied triple therapy (n = 21) with the use of telaprevir (TVR; n = 12) or simeprevir (SVR; n = 9). ResultsTVR was given at the dose 1,500 mg daily (n = 11) with reduced dose of cyclosporine at 25% to 50%, and SVR was given at the dose 100 mg daily with unadjusted cyclosporine, followed by 12 weeks of dual therapy. The early viral response was achieved in 91.7% (n = 11), end of treatment response rate was 91.7% (n = 11), and sustained viral response rate was 83.3% (n = 10) in the TVR group, and respective rates were 88.9% (n = 8), 77.8% (n = 7), and 77.8% (n = 7) in the SVR group. Although granulocyte colony-stimulating factor was not given in the patients with triple therapy, blood transfusion was performed in 7 cases (58.3%) in the TVR group and 1 case (11.1%) in the SVR group. Interferon-mediated graft dysfunction was observed in 4 cases (33.3%) in the TVR group and 3 cases (33.3%) in the SVR group, respectively. The cumulative viral clearance rates in triple (n = 21) and dual (n = 105) therapy were 95.0% and 18.1% at 12 weeks, and 95.0% and 40.0%, respectively, at 24 weeks (P < .01). ConclusionsAlthough careful monitoring for possible adverse events is required during treatment, triple therapy with the use of direct-acting agents are very effective in treating hepatitis C after liver transplantation.

Safety and efficacy of partial splenic embolization in telaprevir-based triple therapy for chronic hepatitis C.

Pegylated-interferon/ribavirin (peg-IFN/RBV) therapy with a protease inhibitor is the standard therapy for genotype 1b chronic hepatitis C. Despite improving treatment outcomes, patients with thrombocytopenia are often difficult to treat because interferon commonly exacerbates thrombocytopenia. In this study, partial splenic embolization (PSE) was performed in patients with hypersplenism-induced thrombocytopenia to determine the effectiveness of this method as a potential treatment. Patients were pretreated with PSE and then received triple combination therapy. The safety and efficacy of PSE was evaluated. Eighteen patients were analyzed, including 12 patients with the interleukin 28B (IL28B) major genotype and 12 patients with the inosine triphosphatase (ITPA) major genotype. The median embolization rate with PSE was 70% (range: 40-85%). PSE increased the patients' platelet counts from 71.5×10(3) /μL (53-99×10(3) /μL) to 121.5×10(3) /μL (70-194×10(3) /μL; p=0.0002). The patients' platelet counts fluctuated above 50×10(3) /μL during the treatment. Specifically, the increase in the platelet count was significantly associated with the ITPA major genotype compared with the minor genotype (p=0.0057 at 2 weeks, p=0.0031 at 3 weeks, and p=0.0148 at 4 weeks). Adherence to peg-IFN-α2b was sufficient (1.38 μg/kg/week). The rapid viral response rate was 72.2% (13/18), the end of treatment response rate was 88.9% (16/18), and the sustained virological response (SVR) rate was 66.7% (12/18). The SVR rate for patients with the IL28B major genotype was 83.3% (10/12). No adverse effect due to PSE pretreatment was found in any patients. Furthermore, no patient discontinued treatment due to thrombocytopenia. PSE, in conjunction with triple combination therapy, is a useful and safe method to treat genotype 1b chronic hepatitis C patients with hypersplenism-induced thrombocytopenia.

Effect of fluvastatin on 24-week telaprevir-based combination therapy for hepatitis C virus genotype 1b-infected chronic hepatitis C.

The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial. Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups. There were 56 men and 60 women, median age 60 years (range, 28-71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P=0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin. In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients.

An open‐label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin

Pegylated interferon (PEG-IFN)/ribavirin combination therapy is the standard-of-care (SOC) treatment for chronic hepatitis C patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. The addition of fluvastatin to SOC treatment has been suggested to be effective for better outcome in retrospective pilot analyses. We investigated whether the combination of fluvastatin with PEG-IFN/ribavirin could actually improve sustained viral response (SVR) in patients with HCV genotype 1b and high viral load. A randomized, open-labeled, controlled study was conducted between July 2008 and December 2009 in 101 chronic hepatitis C patients allocated to PEG-IFN/ribavirin combination therapy with or without fluvastatin. SVR rates were calculated in groups, stratifying host and viral factors. We also analyzed predictive factors for SVR among patients on fluvastatin with multivariate regression analysis. Rapid and early virological, and end of treatment response rates in the fluvastatin group were not significantly different from those in the non-fluvastatin group. Notwithstanding, SVR rate was significantly higher in the fluvastatin group than in the non-fluvastatin group (63.0%vs 41.7%, P = 0.0422). Comparison of the two groups stratifying demographic data and HCV characteristics showed significantly higher SVR rates to more than 80% in males, more than two mutations in the interferon sensitivity determining region (ISDR), and a history of relapse among the fluvastatin group than the non-fluvastatin group. Being male and major genotype IL28B single nucleotide polymorphisms (SNPs) were independent predictive factors for SVR among patients on fluvastatin with multivariate analysis. Fluvastatin-combined with PEG-IFN/ribavirin therapy significantly improves SVR rates in patients with HCV genotype 1b and high viral load. Male and major genotype IL28B SNPs were independent predictors for SVR among patients on fluvastatin combination therapy.

Pharmacokinetics of RO5072759 (GA101) In Patients with Relapsed/Refractory CD20+ Malignant Disease (Phase I/II Study BO20999)

AbstractAbstract 1833 Background and Objective:GA101 is the first type II glycoengineered and humanized monoclonal anti-CD20 antibody to enter clinical trials. BO20999 is an open label multicenter, phase I/II study evaluating GA101 safety, tolerability and pharmacokinetics in patients with relapsed/refractory CD20+ NHL/CLL. Phase I results showed an end of treatment response rate (EOR) of 33% in NHL patients (Salles G. et al, Blood [ASH Annual Meeting Abstracts], Nov 2009; 114: 1704). Phase II results recently reported for indolent NHL showed an EOR of 55% and 17% for GA101 monotherapy given at a high dose (HD) and a low dose (LD), respectively supporting a possible dose-response relationship (Salles G. et al, Haematologica 2010; 95[suppl.2]:229, abs. 0558). Here within, we describe the results of analyses exploring GA101 exposure and response in indolent NHL patients. Study Population and Assessments:Phase I Study: 21 patients with CD20+B-lymphoproliferative disorders including [follicular lymphoma (fNHL), mantle cell lymphoma (MCL), diffused large B cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and lymphoplasmacytoid lymphoma received intravenous GA101 as a flat dose in a safety driven dose escalation 3+3 design (from 50 mg to 2000 mg).Phase II Study: 40 indolent NHL patients were randomized to receive low dose (LD) GA101 (n=18) or a high dose (HD) (n=22). GA101 was given on d1, d8, d22 and q21 days for a total of 9 infusions as a flat dose. In the LD cohort, GA101 was 400 mg; in the HD cohort, d1 and d8 were 1600 mg and subsequently 800 mg thereafter. Pharmacokinetic Assessments:GA101 serum samples were taken prior to and immediately after each infusion, for all eight cycles. Additional serum samples were taken between days 1–21 during cycle 1 and between days 1–25 during cycle 8. Serum levels of GA101 were measured by ELISA. Results:Phase I GA101 PK data: Although a high degree of variability was observed in the GA101 plasma concentrations, due in part to inter-individual differences, mean GA101 plasma concentration increased with dose.Phase II GA101 PK data: As anticipated, higher GA101 plasma concentrations were observed in the HD group compared to the LD group (Figure 1). In the HD group after cycle 2 mean Cmax and Cmin values plateaued whereas in the LD group both mean Cmax and Cmin values continued to increase between cycles 2 and 8. Given there were some responses (n=3) in the LD group, a dose of 400 mg has some biological effects; however target saturation appears incomplete, whereas the HD group indicates sustained target saturation. Responding patients from both dose groups appeared to have higher plasma concentrations compared to non-responding patients (Figure 2). Interestingly, responding patients showed increased plasma concentrations over time whereas there was a decrease in plasma concentrations in the non-responding patients. Moreover, further analysis in the HD group demonstrated that non-responding patients have the highest peak to trough concentration ratios indicating a higher rate of GA101 elimination compared to the responding patients (Figure 3). Overall, these data indicate that responding patients appear to eliminate GA101 slower compared to non-responding patients. Conclusions:Overall, GA101 plasma concentrations appeared to increase with dose in both Phase I (dose escalation) and Phase II parts of BO20999. Accumulation of GA101 levels in plasma was observed from 400/800 mg to 1200/2000 mg dose group which was consistent with target saturation.GA101 plasma profiles indicated that responding iNHL patients appeared to eliminate GA101 slower compared to non-responding iNHL patients. [Display omitted] [Display omitted] [Display omitted] Disclosures:Wenger:Roche: Employment. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria. Morschhauser:Roche: Consultancy, Honoraria. Salles:Roche: Consultancy, Honoraria.

Comparison of Single Agent GA101 In Japanese and European Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (B-NHL) – Results From Two Phase I Studies

AbstractAbstract 4921 Background:Most studies regarding the chimeric anti-CD20-antibody rituximab have reported no ethnic differences including response or safety in B-NHL. GA101 is the first type II, glycoengineered and humanized anti-CD20 monoclonal antibody to enter clinical trials. Results in B-NHL patients have previously been reported from three phase I studies, conducted in Europe, Canada and Japan (Salles 2008, 2010, Sehn 2009, Tobinai 2010), and all have demonstrated good tolerability along with promising activity, with a safety profile largely similar to rituximab when compared to historical rituximab data. Here we report a comparison of the phase I studies BO20999 and JO21900, conducted in Europe and Japan, respectively, to analyze any potential ethnic differences in safety/efficacy. Both studies were conducted in patients with relapsed/refractory B-NHL, with the majority of patients being of indolent histology and both studies used identical drug administration and response assessment schedules. Methods:In both studies GA101 was administered IV as monotherapy (as an absolutely flat dose) on days 1, 8 and 22, and then every 3 wks, for a total of 9 infusions. The dose was escalated using a 3+3 design, with study JO21900 starting at a higher dose of 200/400mg (with doses up to 2,000mg, a dose level judged safe and well tolerated in BO20999 (doses ranging from 50-2, 000mg). Patient and disease characteristics, prior treatments, response rates and safety parameters from both studies were compared. Given the small sample sizes, heterogeneity, the dose-escalation design and the cross-trial comparison, no formal statistical analysis was applied. Results:Patient age and other baseline parameters were substantially similar between the two studies (Table 1). The safety profiles in both studies were comparable, with the most common AEs being infusion-related reactions (86% BO20999; 100% JO21900) of grade 1–2 mainly associated with the first infusion and decreasing with subsequent infusions. Incidence of SAEs were similar (BO20999 [n=4], JO21900 [n=2]). Importantly, no dose-limiting toxicities and no dose reductions were observed in either study. No patients with aggressive histology were enrolled into study JO21900, and Japanese patients were less heavily pretreated (median of 1 vs 4 prior treatments for European patients) and no Japanese patient had received prior autologous stem cell transplant. End of treatment response rates were slightly higher in Japanese study than those in the European study (Table 1).GA101 plasma drug concentrations in both studies were comparable, with the observation of a large inter-patient variability, however, a dose-dependent increase in mean plasma concentrations, increasing with dose, was observed in both studies. Conclusion:These clinical, safety and pharmacokinetic results from two phase I studies suggest that there appears to be no apparent differences between Japanese and European patients with respect to the safety or efficacy of GA101 monotherapy in indolent B-NHL patients, although analyses on larger datasets would be required to confirm these initial results. The slightly higher response rates observed in Japanese patients may be attributable to the small sample size, and a less heavily pre-treated population that comprised of patients solely of indolent histology only.Table 1:Comparison between European and Japanese GA101 Phase 1 studiesBO20999 (Europe)JO21900 (Japan)n2112Median age6457.5Weight (median, kg)7455.5Indolent histology16 (76%)12 (100%)Follicular histology13 (62%)8 (67%)Median previous treatments4 (1-7)1 (1-11)Prior Rituximab20/21 (95%)12/12 (100%)Rituximab refractory02/12 (17%)Prior ASCT11 (52%)0End of treatment response in all patients7/21 (33%)7/12 (58%)CR in all patients4/21 (19%)2/12 (17%)End of treatment response in follicular lymphoma7/13 (54%)6/8 (75%)CR in follicular lymphoma2/13 (15%)2/8 (25%)FcgRIIIa genotypes *n=17*F/F (10), F/V (4), V/V (3)F/F (7), F/V (5)FcgRIIIa genotypes and responseF/F (1 CR, 2 PR, 3 SD, 4 PD), F/V (1 CR, 1 SD, 2 PD), V/V (1 CR, 1 PR, 1 SD)F/F (1 CR, 3 PR, 3 SD), F/V (1 CR, 2 PR, 2 SD) Disclosures:Morschhauser: Roche: Consultancy, Honoraria. Cartron: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hatake: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Wenger: Roche: Employment. Birkett: Roche: Employment. Oya: Chugai Pharmaceutical Co., Ltd.: Employment. Nishima: Chugai Pharmaceutical Co., Ltd.: Employment. Salles: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Meta-analysis Shows Extended Therapy Improves Response of Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Clinical trials provided conflicting results about whether extended duration of treatment with pegylated interferon-alfa (pegIFN-alfa) and ribavirin (more than 48 weeks) improves rates of sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 and slow virologic response. We performed a meta-analysis to determine the overall impact of extended treatment, compared with standard treatment, on virologic response rates in these patients. We performed a literature search to identify randomized controlled trials (RCTs) that included monoinfected, treatment-naive patients infected with HCV genotype 1; data were compared between slow responding patients treated with pegIFN-alfa-2a/b plus ribavirin for 48 weeks and those that received extended treatment (as much as 72 weeks). End points included SVR rates, end-of-treatment (EOT) response and relapse rates; they were calculated according to the DerSimonian-Laird estimate. Six RCTs assessed the benefits of extended treatment with pegIFN-alfa-2a/b and ribavirin in treatment-naive patients with HCV genotype 1 that were slow responders (n = 669). The extended treatment significantly improved SVR rates in slow responders, compared with the standard of care (14.7% increase in overall SVR; 95% confidence interval, 4%-25.5%; P = .0072). Rates of viral relapse were significantly reduced by extended treatment, but EOT response rates were similar. The frequency of voluntary treatment discontinuation, but not of serious adverse events, was significantly increased by extended therapy. Extending the duration of treatment with pegIFN-alfa-2a/b and ribavirin in patients with HCV genotype 1 and a slow response to therapy improves the rate of SVR.

272 EARLY VIRAL RESPONSE OF CONTROLLED-RELEASE INTERFERON ALPHA2B AND RIBAVIRIN VS. PEGYLATED-INTERFERON ALPHA2B AND RIBAVIRIN IN TREATMENT-NAIVE GENOTYPE1 HEPATITIS C: 12 WEEK RESULTS (SELECT-2 TRIAL)

Aims: Recently, several clinical trials analyzed if extended duration of treatment with pegylated interferon-alfa and ribavirin over 48 weeks can improve sustained virologic response (SVR) rates in HCV genotype 1-infected patients with slow virologic response. Because results of these clinical trials are conflicting, we performed a metaanalysis to determine the overall impact of extended treatment compared to standard treatment on virologic response rates in treatment-naive HCV genotype 1 slow responders. Methods: Literature search was performed independently by two observers using Pub Med, EMBASE, CENTRAL and abstracts presented in English at international liver and gastroenterology meetings. Randomized controlled clinical trials (RCTs; but studies that re-analyzed data retrospectively RCTs were also allowed) were considered if they included monoinfected treatment-naive HCV genotype 1 patients and compared treatment with pegIFN-alfa 2a or 2b in combination with ribavirin for 48 weeks versus extended treatment (up to 72 weeks) in slow responders. Primary and secondary end points were SVR rates and end-of-treatment (EOT) and relapse rates, respectively. In the present meta-analysis, study endpoints were summarized with a DerSimonian-Laird estimate for binary outcome basing on a random effects model. Results: Literature search yielded seven RTCs addressing the benefit of extended treatment with pegylated interferon-alfa and ribavirin in treatment-naive HCV genotype 1 slow responders. In total, 1330 slow responders were included in our meta-analysis. We show that extended treatment duration compared to the standard of care significantly improves SVR rates in HCV genotype 1 slow responders (12.4% improvement of overall SVR rate, 95%CI 0.055– 0.193, P =0.0005). In addition, we show that rates of viral relapse were significantly reduced by extended treatment (24.1% reduction of relapse, 95%CI −0.3332 to −0.1487, P < 0.0001), whereas no significant impact of extended treatment on EOT response rates was found. Though extended treatment was burdened with an enhanced rate of premature treatment discontinuation due to interferonalfaand ribavirin-related side effects, the frequency of serious adverse events was not increased. Conclusions: Treatment extension in HCV genotype 1 slow responders can improve SVR rates in difficult to treat patients and should be considered in patients who need to be treated before specific antivirals will be approved.

271 EXTENDED TREATMENT OF TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS C VIRUS (HCV) GENOTYPE 1-INFECTION AND SLOW RESPONSE TO PEGYLATED INTERFERON-ALFA AND RIBAVIRIN: A META-ANALYSIS

Aims: Recently, several clinical trials analyzed if extended duration of treatment with pegylated interferon-alfa and ribavirin over 48 weeks can improve sustained virologic response (SVR) rates in HCV genotype 1-infected patients with slow virologic response. Because results of these clinical trials are conflicting, we performed a metaanalysis to determine the overall impact of extended treatment compared to standard treatment on virologic response rates in treatment-naive HCV genotype 1 slow responders. Methods: Literature search was performed independently by two observers using Pub Med, EMBASE, CENTRAL and abstracts presented in English at international liver and gastroenterology meetings. Randomized controlled clinical trials (RCTs; but studies that re-analyzed data retrospectively RCTs were also allowed) were considered if they included monoinfected treatment-naive HCV genotype 1 patients and compared treatment with pegIFN-alfa 2a or 2b in combination with ribavirin for 48 weeks versus extended treatment (up to 72 weeks) in slow responders. Primary and secondary end points were SVR rates and end-of-treatment (EOT) and relapse rates, respectively. In the present meta-analysis, study endpoints were summarized with a DerSimonian-Laird estimate for binary outcome basing on a random effects model. Results: Literature search yielded seven RTCs addressing the benefit of extended treatment with pegylated interferon-alfa and ribavirin in treatment-naive HCV genotype 1 slow responders. In total, 1330 slow responders were included in our meta-analysis. We show that extended treatment duration compared to the standard of care significantly improves SVR rates in HCV genotype 1 slow responders (12.4% improvement of overall SVR rate, 95%CI 0.055– 0.193, P =0.0005). In addition, we show that rates of viral relapse were significantly reduced by extended treatment (24.1% reduction of relapse, 95%CI −0.3332 to −0.1487, P < 0.0001), whereas no significant impact of extended treatment on EOT response rates was found. Though extended treatment was burdened with an enhanced rate of premature treatment discontinuation due to interferonalfaand ribavirin-related side effects, the frequency of serious adverse events was not increased. Conclusions: Treatment extension in HCV genotype 1 slow responders can improve SVR rates in difficult to treat patients and should be considered in patients who need to be treated before specific antivirals will be approved.

Preliminary report on safety and response rate of pegylated interferon-alpha 2a (pegasys) in genotype D chronic hepatitis B patients in Iran.

Aim : The aim of study was to determine the preliminary result of treatment with pegasys in Iranian chronic hepatitis B patients (with genotype D) referred to Tehran Hepatitis center (THC). Background : The genotype of HBV and ethnicity of the patients can affect the response rate to pegasys. Patients and methods : During 2006-2008, 12 Patients with naive chronic hepatitis B (genotype D) that referred to THC and candidate for treatment were consequently enrolled in this cross sectional study. All of the patients signed the written consent to enter the study. They were treated weekly with 180 microgram of pegylated interferon- alpha 2a (pegasys) subcutaneously. They were visited monthly during their treatment and follow up course in THC. The safety of treatment, the end of treatment response, the relapse rate and the sustained virologic response were measured in these patients. Results : The end of treatment response rate was 83.3% in total. In patients who had end treatment response, the relapse rate was 50% (4/8) among HBeAg negative patients and 75% (3/4) among HBeAg positive patients. The sustained virologic response rate in this study was 41.6%. Conclusion : Our study showed that after treatment with pegasys, the genotype D chronic hepatitis B patients had an acceptable sustained virologic response rate (More than 30%). But the influence of HBV genotype on treatment response with pegasys needs to be reevaluated in these patients in future studies. In addition other patient-specific characteristics like genetic aspects should be taken into consideration.

Association of Genetic Variation in Il28B with Hepatitis C Treatment-Induced Viral Clearance in the Chinese Han Population

Genome-wide association studies have recently shown that the rs12979860 polymorphism in IL28B is associated with the response to chronic hepatitis C treatment. The aim of this study was to investigate whether rs12979860 could be used as a predictive marker for end-of-treatment response (ETR) or sustained virological response (SVR) in the Chinese Han population. The rs12979860 genotype was detected in 259 individuals infected with HCV by DNA sequencing. Among them, 120 patients were administered complete pegylated interferon-α and ribavirin combination therapy and 92 patients were followed for 24 weeks after the cessation of treatment and were divided into different groups according to outcomes of treatment. The rs12979860 genotype CC was the primary genotype (87.64%, 227/259) and genotype TT was found in only one individual within this cohort. The patients with the rs12979860 genotype CC had higher rates of ETR (P=0.0044) and SVR (P=0.0046) than the patients with N-CC (CT or TT). In multivariate analyses, the rs12979860 genotype CC was associated with a substantial difference in rates of achieving ETR (odds ratio [OR] 8.983, 95% confidence interval [CI] 2.173-37.145; P=0.0024) and SVR (OR 24.298, 95% CI 2.27-259.90; P=0.0083). This study demonstrated for the first time that the rs12979860 variation in IL28B could be a predictor of ETR and SVR in Chinese Han patients infected with HCV. The high frequency of the rs12979860 genotype CC might explain why the SVR rate is higher than that of the average global population.