Ribavirin Dose Research Articles

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients.

To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients. We retrospectively compared the liver biopsies of well-matched HCV LT recipients under calcineurin inhibitors (CNI group, n = 21) and mycophenolate (MMF group, n = 15) monotherapy, with those patients who successfully withdrawn immunosuppression (IS) therapy from at least 3 years (TOL group, n = 10). To perform the well-matched analysis, all HCV transplanted patients from December 1993 were screened. Only those HCV patients who reached the following criteria were considered for the analysis: (1) at least 3 years of post-operative follow-up; (2) patients with normal liver graft function under low dose CNI monotherapy (CNI group); (3) patients with normal liver graft function under antimetabolite (Micophenolate Mofetil or coated mycophenolate sodium) monotherapy (MMF group); and (4) recipients with normal liver function without any IS. We excluded from the analysis recipients who were IS free or under monotherapy for < 36 mo, recipients with cirrhosis or with unstable liver function tests. Thirty six recipients were enrolled in the study. Demographics, clinical data, time after LT and baseline liver biopsies were comparable in the three groups. After six years of follow-up, there was no worsening of hepatic fibrosis in the MMF group (2.5 ± 1.5 Ishak Units vs 2.9 ± 1.7 Ishak Units, P = 0.5) and TOL group (2.7 ± 10.7 vs 2.5 ± 1.2, P = 0.2). In contrast, a significant increase in the fibrosis score was observed in the CNI group (2.2 ± 1.7 vs 3.9 ± 1.6, P = 0.008). The yearly fibrosis progression rate was significantly worse in the CNI group (0.32 ± 0.35) vs MMF group (0.03 ± 0.31, P = 0.03), and TOL group (-0.02 ± 0.27, P = 0.02). No differences have been reported in grading scores for CNI group (2.79 ± 1.9, P = 0.7), MMF group (3.2 ± 1.5, P = 0.9) and TOL group (3.1 ± 1.4, P = 0.2). Twenty four patients were treated with low dose ribavirin (8 TOL, 7 MMF, 9 CNI). The hepatitis C titers were comparable in the three groups. No episodes of rejection have been reported despite differences of liver function test in the three groups during the observational period. IS withdrawal and MMF monotherapy is safe and seems to be associated with the slowest fibrosis progression in HCV LT recipients.

How to optimize current treatment of genotype 2 hepatitis C virus infection

The standard of care (SOC) for hepatitis C virus (HCV) genotype 2 is pegylated interferon (PEG-IFN) plus ribavirin (RBV). Even though most patients can be cured with this therapy after 24weeks, tailoring treatment can improve its safety and efficacy in special populations. Thus, shortening treatment together with a weight-based RBV dosing approach has been considered satisfactory in patients with positive predictors of response. With the development of the direct antiviral agents (DAAs), shorter, better tolerated and more efficient treatments for HCV genotype 2 will become available, including interferon-free regimens. Until these new treatments are released, the decision to treat patients with HCV genotype 2 with currently approved drugs or to wait for future options must be made, taking into account the stage of fibrosis.

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study

IntroductionLess than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV). ObjectivesTo assess the impact of high doses of RBV on SVR in patients with G3 and HVL. MethodsNinety-seven patients were randomized to receive peginterferon α-2a+RBV 800mg/day (A; n=42) or peginterferon α-2a+RBV 1600mg/day+epoetin β 400IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600mg/day)+epoetin β (B2; n=13). ResultsRVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of −2.5% (−21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%. ConclusionsG3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609).

The End-of-Treatment Ribavirin Concentration Predicts Hepatitis C Virus Relapse

The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment. Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.

Adjuvant epoetin‐β with peginterferon‐α and ribavirin in Japanese ribavirin‐intolerant relapsed patients with chronic hepatitis C genotype 2

Erythropoietin is widely used in the USA and some other Western countries to maintain doses of ribavirin during peginterferon/ribavirin-based treatment for chronic hepatitis C virus (HCV) infection. However, the impact of erythropoietin on sustained virological response (SVR) is unclear. Here, we report the cases of three Japanese ribavirin-intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin. Three women aged 50, 64 and 68 years with chronic HCV genotype 2 received retreatment with peginterferon-α and ribavirin. During their prior therapy, HCV RNA became negative according to real-time polymerase chain reaction at weeks 4-8 in all three patients; however, the total dose of ribavirin was 18.1-30.6% lower than the planned dose, and HCV RNA relapsed post-treatment. At present, epoetin-β 24 000 IU was introduced at weeks 2 or 3 of dual-combination therapy, resulting in a less than 4.2% reduction in the total dose of ribavirin. HCV RNA became negative at weeks 4-8, and all patients achieved SVR. Until the next-generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for ribavirin-intolerant relapsed patients.

In routine clinical practice, few physicians use early viral kinetics to guide HCV dual therapy treatment decisions

PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response (VR). This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR (cEVR), partial EVR (pEVR), no RVR/EVR], using standard criteria. The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA≤400 000 IU/ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA>400 000 IU/ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience.

Feasibility of Telaprevir-Based Triple Therapy in Liver Transplant Patients with Hepatitis C Virus: SVR 24 Results

Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy. Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions. This retrospective analysis provides evidence that - with respect to SVR 24 - liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.

Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir

In clinical trials with telaprevir (TLV) and boceprevir (BOC) renal impairment was not reported as a relevant adverse event. The PAN study is a noninterventional study enrolling patients treated with peginterferon alfa-2a/ribavirin (PEG/RBV) with or without TVL or BOC. Here we restrict the analysis to hepatitis C virus genotype 1 patients having completed 12 (n = 895) or 24 weeks (n = 591) of treatment. For estimation of glomerular filtration rate (eGFR) the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was chosen. Patients on TLV 38/575 (6.6%) and BOC 10/211 (4.7%) more frequently experienced a decrease in eGFR to <60 mL/min compared to patients on PEG/RBV 1/109 (0.9%) (P < 0.05). Risk factors associated with eGFR <60 mL/min in multiple logistic regression analysis were age (P < 0.001), arterial hypertension (P < 0.05), higher serum creatinine at baseline (P < 0.001), and being on triple therapy with TLV or BOC (P < 0.01). Patients with an eGFR of <60 mL/min had a lower absolute mean hemoglobin at week 12 compared to patients with an eGFR >60 mL/min (9.7 g/dL ± 1.4 g/dL versus 11.0 g/dL ± 1.7 g/dL) (P < 0.001). Most patients on TLV with a decrease of eGFR <60 mL/min showed a marked improvement in renal function after discontinuation of TLV. Renal impairment has not been reported as a safety signal in clinical trials with TVL or BOC. However, in this large cohort including patients with risk factors for renal impairment a marked decline in renal function was observed in about 5% of patients on triple therapy. In addition to being a safety concern, substantial ribavirin dose reductions have to be considered in these patients, as anemia was more pronounced in patients with impaired renal function.

Abstract A154: Inhibition of eIF4E with Ribavirin suppresses EMT and breast cancer invasiveness.

Abstract The eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that drives cellular transformation, tumorigenesis and metastasis by facilitating nuclear export and translation of specific mRNAs, including cyclins, c-myc, matrix metalloproteinases (MMPs), VEGF and others. eIF4E is commonly overexpressed and/or activated in cancer, and we and others have shown that high eIF4E expression in primary and metastatic breast cancers correlates with poor prognosis. Recent studies have shown that Ribavirin, an old antiviral drug, can inhibit oncogenic transformation mediated by eIF4E and exert antitumor activity in cancer cell lines, animal models, and patients with acute myeloid leukemia (AML) that express elevated eIF4E. Dramatic clinical responses in AML correlated with reduced eIF4E level and activity. Ribavirin is thus the first drug to date with antitumor activity linked to direct inhibition of eIF4E in patients. In this study, we have evaluated the potential anti-metastatic activity of ribavirin. We first assessed the role of eIF4E in the epithelial-to-mesenchymal transition (EMT), a process enabling metastasis. We showed that either knockdown of eIF4E or Ribavirin treatment attenuate EMT induced by TGFβ in normal mammary epithelial cells, blocking the increase of mesenchymal markers as well as MMP-9 secretion and decreasing cell migration and invasion. We then studied the effects of eIF4E targeting on triple negative breast cancer cells in vitro and in vivo. We have previously shown that ribavirin suppresses breast cancer cell proliferation and this is associated with a decrease in known eIF4E targets. Using human and murine cell lines, we further observed a reduction in several mesenchymal markers, including N-cadherin, fibronectin and snail, following knockdown or chemical inhibition of eIF4E. Moreover, ribavirin significantly reduced tumor cell motility and invasion through Matrigel. Interestingly, overexpression of snail in MDA-MB-231 cells blunts their response to ribavirin, suggesting its involvement downstream of eIF4E. The activity of ribavirin against mammary tumors in vivo was assessed in two syngeneic mouse models, MT2186 and 66cl4, which form tumors in FVB and Balb/c mice, respectively. A non-toxic and clinically relevant dose of Ribavirin caused a striking reduction in MT2186 tumor growth, which correlated with reduced Ki-67 staining and reduced clonogenic potential of cells isolated from ribavirin treated tumors. Growth of the more aggressive and highly metastatic 66cl4 tumors was modestly affected; with only a slight delay in primary tumor growth. However, preliminary data suggest that ribavirin significantly suppresses the formation of 66cl4 lung metastases. Importantly, we measured MMP levels in plasma and found a selective increase in MMP-9 with growth of tumors over time, which was suppressed in the ribavirin treated mice. Future studies will further define the mechanism responsible for the anti-metastatic activity of ribavirin in this model. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A154. Citation Format: Audrey Emond, Sonia V. Del Rincon, Bonnie Huor, Filippa Pettersson, Wilson H. Miller. Inhibition of eIF4E with Ribavirin suppresses EMT and breast cancer invasiveness. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A154.

Analysis of Site Performance in Academic-based and Community-based Centers in the IDEAL Study

To evaluate differences in metrics of quality and site performance in academic and community sites participating in a multicenter study. In the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy study, the participation of 76 academic-based and 42 community-based US centers provided an opportunity to evaluate various metrics of quality and site performance. A secondary data analysis of the Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy study was performed. There were 3070 treatment-naive, hepatitis C virus genotype 1 infected patients were included. We retrospectively evaluated rates of screen failure, completion, and discontinuation of treatment and follow-up, treatment adherence, and virologic response by site type. Of the patients screened, 63% and 37% were in academic and community centers, respectively. Screen failure rates were similar (30% to 32%). End-of-treatment response, relapse, and sustained virologic response (SVR) rates in academic and community centers did not differ. SVR was achieved in 40% of patients at academic sites and 39% at community sites. Adherence to ≥80% of peginterferon-α and ribavirin dosing for ≥80% assigned duration was also similar (46% in academic and 47% in community centers). In both academic and community centers, 54% of patients completed treatment; there were similar discontinuation rates for treatment failure and adverse events. There were no significant differences in adherence, adverse events, rates of discontinuation, on-treatment virologic response, and SVR when comparing academic and community sites. The performance of academic-based and experienced community-based sites in clinical trials is largely similar for the treatment of chronic hepatitis C.

Safety in the clinical practice of the triple therapy with telaprevir in chronic hepatitis C

To study the safety of triple therapy with telaprevir and the time of appearance of the RAM in the treatment of hepatitis C. A retrospective observational study (January 2012- June 2013) of patients with HCV genotype 1 who had completed 12 weeks of triple therapy with telaprevir. The following variables were needed to characterize patients, and those relating to the treatment received. The classification of ADR was performed according to criteria of the SIDA Division 1.0. We included 88 patients (78% male), 75% cirrhotic patients. 40.9% were coinfected with HIV. The main ADR (incidence > 40%) including all grades: haematological toxicity, fatigue, hyperuricemia, hyperbilirubinemia and pruritus. Serious ADR (incidence > 15%): thrombocytopenia, anemia and neutropenia. 3.4% had severe toxicodermia. 51.1% required ribavirin dose adjustment, blood transfusions 13.6%, and 28.4% exogenous erythropoietin. The 8% required hospitalization motivated by treatment toxicity. The treatment was stopped for toxicity in 6.8% of patients: 3 severe toxicodermia, 2 severe haematological toxicity, and 1 severe emesis. Thrombocytopenia and hyperbilirubinemia occurred at an early stage in its higher degree of toxicity, while the other ADR presented progression longer periods. The study shows a superior toxicity profile to that described in clinical trials, mainly with regard to hematologic toxicity, and predicts a time range of highest probability of occurrence of ADR.

Efficacy and safety of peginterferon plus ribavirin for patients aged ≥ 65 years with chronic hepatitis C: A systematic review and meta-analysis

Studies up to August 30, 2012 of the efficacy and safety of peginterferon plus ribavirin therapy in CHC patients aged≥65 years were systematically identified in PubMed, Ovid, Web of Knowledge and Cochrane Library databases. A meta-analysis was performed using both fixed- and random-effects models based on heterogeneity across studies. The overall sustained virological response (SVR) in CHC patients aged≥65 years was significantly lower than in patients aged<65 years on both intention-to-treat (ITT; 42.0% vs. 60.1%, respectively; P<0.00001) and per-protocol (PP; 54.4% vs. 67.4%, respectively; P=0.002) analyses, including treatment-naïve patients. Subgroup analysis showed that patients≥65 years with either hepatitis C virus (HCV) genotype 1/4 or 2/3 had lower SVR rates than younger patients. No statistically significant differences were observed between the two groups in terms of rapid virological response (RVR) and early virological response (EVR) rates (both P≥0.05). However, the end-of-treatment virological response (ETR) rate was lower in patients≥65 years, who also had a significantly higher risk of relapse than those aged<65 years (39.8% vs. 26.9%, respectively; P<0.00001). The discontinuation rate in the older patients was also significantly higher than in the younger patients (25.5% vs. 14.8%, respectively; P<0.00001). Ribavirin dose reduction in the older patients treated with peginterferon plus ribavirin was also significantly higher than in younger patients (44.5% vs. 32.8%, respectively; P<0.00001). Peginterferon plus ribavirin therapy was effective for older patients with CHC, particularly those with HCV genotype 2/3. Response-guided therapy can be used for older patients with genotype 1/4, but such patients had poorer treatment adherence, leading to poorer treatment efficacy.

Rates and predictors of response to anti‐viral treatment for hepatitis C virus inHIV/HCVco‐infection in a nationwide study of 619 patients

The effectiveness of anti-viral treatment for hepatitis C virus (HCV) in HIV/HCV co-infected patients in 'real world', clinical practice is unclear. To determine the rates and predictors of sustained virological response (SVR) to anti-viral treatment for HCV with pegylated interferon (PEG-IFN) and ribavirin in HIV/HCV co-infected patients. We identified all HIV/HCV co-infected patients who received anti-viral treatment with PEG-IFN and ribavirin in the Veterans Affairs healthcare system nationally between 2002 and 2009 (n = 665). Sustained virological response was achieved in 21.6% overall, 16.7% among patients with genotype 1 HCV (n = 491) and 44% among patients with genotype 2 or 3 HCV (n = 116). Among genotype 1-infected patients, characteristics that were negatively associated with SVR independently included baseline HCV viral load >2 million IU/mL [adjusted odds ratio (AOR) 0.41, 95% CI 0.2-0.7], Black race [AOR 0.56 (0.3-0.96)], diabetes [AOR 0.42 (0.2-0.9)], baseline anaemia [AOR 0.42 (0.2-0.97)], serum aspartate aminotransferase/alanine aminotransferase ratio ≥1.2 [AOR 0.48 (0.2-0.97)] and use of zidovudine [AOR 0.41 (0.2-0.9)]; characteristics positively associated with SVR included a starting dose of ribavirin ≥1000-1200 mg/day [AOR 2.0 (1.1-3.7)] and erythropoietin use during treatment [AOR 2.9 (1.6-5.0)]. Among genotype 2 or 3 infected patients, only erythropoietin use was an independent predictor of SVR [AOR 3.1 (1.2-7.8)], while a starting dose of ribavirin >800 mg/day was not associated with SVR. Sustained virological response rates achieved with PEG-IFN and ribavirin in HIV/HCV co-infected patients are low in clinical practice. The use of erythropoietin was the most important, modifiable factor associated with SVR.

Eltrombopag Increases Platelet Numbers in Thrombocytopenic Patients With HCV Infection and Cirrhosis, Allowing for Effective Antiviral Therapy

Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. Patients with HCV infection and thrombocytopenia (platelet count <75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Non-ischemic Cardiomyopathy Secondary to Pegylated Interferon in a Patient with Chronic Hepatitis C

Purpose: Reversible cardiomyopathy is a side effect of interferon treatment, typically described as being associated with high-dose standard interferon. Pegylated INF has a polyethylene glycol molecule attached to the protein, which results in a reduction in its rate of absorption, renal clearance, and immunogenicity following subcutaneous injection. We present a rare case of PEG interferon-induced dilated cardiomyopathy. A 65-year-old female with hepatitis C (HCV), mononeuritis multiplex, mixed cryoglobulinemia, and hypertension presented with complaints of shortness of breath with minimal exertion, which was gradually worsening. She denied any chest pain, palpitations, fever, chills, blood loss, weight loss, or history of smoking. She was started on treatment for HCV in June of 2012, with telapravir, PEG interferon, and ribavirin. Her viral load was detectable at week four, and undetectable at weeks 12 and 24. Her renal function was normal at the start of treatment. During the therapy, her renal function started to deteriorate. Doses of ribavirin and interferon were reduced secondary to her anemia and neutropenia, respectively. Despite dose reduction, treatment was stopped at week 33 due to treatment intolerance. Prior to treatment, the patient had a cardiac catheterization, which showed an ejection fraction (EF) of 50% and non-obstructive coronary artery disease. An echocardiogram done in following treatment showed an EF of 30-35%, with moderate mitral regurgitation (MR) and global left ventricular hypokinesia, stage three diastolic dysfunction, left ventricular dilatation, moderate left atrial dilatation, trace tricuspid regurgitation, and a pulmonary artery pressure of 40 mmHg. A transesophageal echocardiogram (TEE) confirmed the global hypokinesia, and the EF had decreased to 15-20%, with moderate MR. Repeat cardiac catheterization showed global hypokinesia, patent coronary arteries, and an EF of 25-30%. The right ventricular systolic pressure was 41 mmHg. Cryoglobulins were absent, and the rheumatoid factor had decreased to 45 from 200 prior to treatment. An autoimmune work-up was negative. The patient denied any flu-like illness during treatment. A myocardial biopsy was not performed to confirm the diagnosis; however, after ruling out other causes of cardiomyopathy, we attributed the cardiomyopathy to interferon therapy. We believe that the deterioration in renal function may have caused elevated concentrations of interferon, resulting in cardiotoxicity. The sudden worsening of the cardiomyopathy and its chronology in relation to the use of pegylated interferon and deteriorating renal function further support our impression.

HCV Triple Therapy, The Non-study Experience: A Single Center Analysis Comparing African American to White Americans

Purpose: To evaluate qualitative and quantitative differences between African Americans and White Americans in the treatment of HCV in a non-study based setting; the real world experience. Methods: A retrospective case study analysis at a single center that evaluated the efficacy of triple HCV therapy in non study setting. Clinical response and quantitative laboratory values were compared between African-American and non African-American patients throughout the duration of treatment. Patients were included if they started triple therapy treatment after July 2011 and are not a part of any other clinical/pharmaceutical trials. Results: African-Americans were found to have significantly higher BMI and HCV RNA quantitative viral loads at initiation of treatment with triple therapy (either boceprevir or telaprevir; Table 1). Throughout the course of treatment, African Americans had a greater percentage decrease in their baseline hemoglobin and platelet count, and a corresponding reduction in their baseline ribavirin dose. However, treatment outcomes (defined as virus negative at the conclusion of treatment) were not found to be statistically significant between African American and White Americans. A subset analysis (Table 2) revealed that patients who were virus negative at the end of treatment (either telaprevir or boceprevir) were less likely to have received blood transfusions throughout the duration of treatment.Table: Table. HCV triple therapy—African vs white AmericansTable: Table. Treatment outcomesConclusion: Treatment dosages of ribavirin are based upon a patients weight, which corresponds with BMI. Higher doses of ribavirin are more likely to cause cytopenia compared to smaller doses of ribavirin. As a result, patients with higher BMI are more likely to have decreased hemoglobin and platelet counts. In the event a patient develops severe cytopenia, blood transfusion may be necessary. As evidenced in this study, blood transfusion was statistically significant in treatment outcomes - if a patient requires blood transfusions, they are less likely to complete treatment and achieve virus negativity. Larger studies, with greater power, are needed in order to explore other prognostic indicators in the treatment of chronic HCV.

Management of Drug Interactions and Side Effects in Patients with Chronic Hepatitis C Receiving Triple Therapy

Purpose: Triple therapy with pegylated interferon (IFN), ribavirin (RIB), and boceprevir (BOC) has been shown to increase sustained virological response in patients with chronic hepatitis C. However, health care providers are faced with the management of drug interactions and side effects of this new therapeutic regimen. The purpose of this research study is to collect data regarding the management of the drug interactions and side effects in patients with chronic HCV receiving this therapy. Methods: A prospective chart review of 26 patients with hepatitis C, receiving triple therapy with pegylated interferon, ribavirin, and boceprevir was conducted. Pegylated IFN, RIB dosages, hemoglobin (Hgb), white blood cell count (WBC), and platelets levels were reviewed. Anemia was defined as either symptomatic decreases from baseline Hgb or Hgb < 10.5 g/dL, while leukopenia was defined as WBC < 4.0 K/mm3. Side effects were recorded at the time of the visit. Concomitant medication changes occurred at the initial visit and were monitored during the initial 24 weeks of therapy. Results: Mean age of this cohort (17 white, five African-American, four Hispanic) was 57.9 ± 4.9 years. Average initial viral load (VL) was 4.04 million (m) (0.002 - 22.0 m); initial platelet count was 164 K ± 42 K; initial fibrosis stage was 2.5 ± 0.94. Initially, patients received pegylated interferon (IFN) [(IFN 180 μg, n=20), (150 μg n=2), (135 μg, n=2), 120 μg, n=2)], [ribavirin (1200 mg, n = 18), (1000 mg, n=4), (800 mg, n=3), (600 mg, n=1)], and boceprevir 800 mg orally, three times per day. Laboratory values decreased during the initial 24 weeks (Hgb, 15.4 to 10.9 g/dL), (platelets 164 to 124K), and (WBC, 5.9.to 2.7 K/mm3). The average amount of pegylated interferon and ribavirin received also decreased (IFN 127 μg and ribavirin 682 mg) at week 24. Three patients relapsed >24 weeks, and two patients were detected at 24 weeks. The side effects included: flu-like syndromes (n=19), rash (n=17), diarrhea (n=2), nausea/vomiting (n=10), anemia (n=26), and leukopenia (n=26). The most frequent drug interactions requiring discontinuations, reductions, or close monitoring involved the following: phosphodiesterase inhibitors, tramadol, and simvastatin. Conclusion: The majority of patients in this small cohort cleared their virus. Reductions in pegylated interferon and ribavirin were common among the HCV patients with fibrosis; however, virological response was 81% in patients who did not fail or discontinue medications. Initial changes in medication were common in this patient cohort.Table 1

Telaprevir with Adjusted Dose of Ribavirin in Naive CHC-G1: Efficacy and Treatment in CHC in Hemodialysis Population TARGET C Trial: A Placebo Randomized Control Clinical Trial

Purpose: The prevalence of chronic hepatitis C (CHC) in hemodialysis population is 3%. Standard of care (SOC) offers reduced dose of Peg IFN Alfa (p-IFNα) and reduced ribavirin (RBV) doses eliciting sub-optimal SVR of 27%. Morbidity and mortality of CHC has impact on liver kidney transplant and graft failure. Triple therapy is SOC in CHC patients. Telaprevir is not cleared renally, and hence, is safe in the hemo-dialysis population. This study evaluated the efficacy of triple therapy with telaprevir, adjusted dose of RBV, and p-IFNα in naïve CHC-G1 (CHC genotype 1) individuals on hemodialysis as a respond guided therapy (RGT). Methods: A total of 35 naïve CHC-G1 were recruited and subdivided into two sub-groups. Group A - (n=18): Received p-IFNα 135 mcg once weekly, telaprevir 750 mg, two tablets; TID for 4 days, and three tablets BID post-dialysis for 3 days, along with RBV 400 mg daily for 12 weeks, followed by p-IFNα 135 mcg plus RVB 400 mg till 24 weeks of duration. Group B - (n=17): Received p-IFNα 135 mcg once weekly with telaprevir 750 mg two tablets; TID for 4 days, and three tablets BID post-dialysis for 3 days (same as Group A) with RBV 200 mg for 12 weeks, followed by p-IFNα 135 mcg with RBV 400 mg till 48 weeks. The IL28B was evaluated for all individuals. Hematological, liver, and renal parameters were followed regularly during the trial. Viral load was followed to evaluate for response-guided therapy (RGT) in all individuals. Results: See table (VRVR - very rapid virological response; ETVR - end to treatment virological response.) Conclusion: This study demonstrates higher SVR comparing traditional SOC on hemodialysis CHC-G1 patients. The extended 48 weeks of therapy showed no added benefits. Multi-center trials to follow.Table. Results

Comparison of Adverse Outcomes of Telaprevir or Boceprevir in Combination with Peginterferon alfa/Ribavirin versus Peginterferon alfa/Ribavirin: Postmarketing Experience in Canada

Purpose: We compared the incidence and management of adverse events (AEs) experienced by patients in Canada during post-marketing treatment for HCV genotype 1 with boceprevir (B) or telaprevir (T) in combination with PegIFN-alfa/ribavirin (PR) vs. PR alone. Methods: Gastroenterologists, hepatologists, and infectious disease specialists were invited to complete an online questionnaire to capture safety-related outcomes of their most recent patients who started therapy from June, 2011 to November, 2012, and at least 3 months prior to data capture. Authors were blinded to the identities of physicians and patients. Patients had to have tested positive for anti-HCV antibody and HCV RNA level ≥10,000 IU/mL for at least 6 months. Patients infected with other HCV genotypes or HIV were excluded. Results: A total of 28 physicians reported data on 217 patients treated with PR (n=83), B+PR (n=61), or T+PR (n=73). The majority of patients (77%) were treatment-naïve. Patients with baseline METAVIR scores F2-F4 were more likely to be treated with B+PR or T+PR. Compared to PR, B+PR and/or T+PR were associated with a higher incidence of any AE (69%/82% vs. 52%), anemia (51%/66% vs. 45%), Hb<100 g/L (26%/43% vs. 14%), Hb<85 g/L (7%/13% vs. 1%), rash (10%/41% vs. 7%), anorectal events (2%/25% vs. 0%), and neutropenia (15%/18% vs. 10%). Management of anemia in patients treated with PR, B+PR, and T+PR included ribavirin dose adjustment (11%, 33%, 49%), epoetin alfa (13%, 28%, 16%), transfusion (2%, 7%, 4%), and/or acute care (2%, 7%, 8%). Differences in the usage of epoetin alfa may be explained by differences in clinical course, stage of fibrosis, use of other management strategies, and/or reimbursement limitations in different provinces. Compared to PR, B+PR/T+PR were associated with a higher number of ribavirin dose adjustments and administration of higher doses of epoetin alfa for longer periods of time. T+PR was associated with higher incidence of grade ≥2 rash than B+PR/PR (14% vs. 2%/4%), requiring more frequent treatment with antihistamines and corticosteroids. One T+PR patient with rash received acute care and was admitted to hospital. Compared to B+PR and PR, T+PR was associated with a higher number of office visits within two months of initiation, as well as longer time spent with the physician per visit. Overall, 1%, 5%, and 5% of patients treated with PR, B+PR, and T+PR discontinued therapy due to treatment-associated AEs. Conclusion: Patients in Canada treated with B or T in combination with PR experienced more frequent and severe AEs, which required medical intervention and discontinuation of treatment. Treatment with B and T also increased utilization of medical resources. Disclosure - Dr. Morris Sherman - honoraria from Roche, Merck, Vertex, Janssen, Boehringer Ingelheim, AbbVie, and Gilead. Dr. Alnoor Ramji - honoraria from Roche, Merck, Vertex, Janssen, Boehringer Ingelheim, and Gilead. Dr. David Sealey is an employee of Janssen Inc. This research was supported by an industry grant from This research was funded by Janssen Inc. Analysis of results and preparation of the abstract were performed jointly by the authors, including Dr. David Sealey who is an employee of Janssen Inc. Dr. Morris Sherman is the lead author.

Triple Therapy Treatment Outcomes in Patients with Chronic Hepatitis C at a Referral Center in South Florida

Purpose: The goal of this study is to evaluate the efficacy and safety of triple therapy antiviral treatment for individuals with hepatitis C in a retrospective study at a South Florida referral center. Methods: Sixty genotype 1 (GT 1) individuals were included in this study (33 males, 27 females). Mean age was 52 years, with a range of 21 to 73, including 37% over the age of 60. Peginterferon alpha-2a/2b (PEG-IFN), ribavirin (RBV) and telaprevir/boceprevir were administered to each patient. Dosage was tailored to patient response. Total treatment duration ranged from 24 weeks to 48 weeks. Patients were monitored during treatment and up to six months post treatment. Results: Among 60 subjects, 47 (78%) achieved SVR (sustained virological response) 24 weeks after treatment completion. There is a strong correlation between lower BMI and early virological response. Relapse rate was 10%, and the overall discontinuation rate was 12%. Sixty-eight percent suffered from major depression, and 5% suffered from extreme psychiatric conditions. Fourteen percentexperienced retinopathy and ocular deficiencies, which subsided post treatment. Males were more susceptible to thrombocytopenia, while females were more susceptible to lymphocytopenia. One case resulted in idiopathic thrombocytopenic purpura, which prevented further treatment. Six (10%) patients had dermatological symptoms, including one case of cutaneous sarcoidosis. Overall, 11 (18%) patients were hospitalized through the course of triple therapy treatment, a majority of whom required blood transfusions. Conclusion: The side effects of triple therapy are substantial, and a decision to begin treatment must effectively weigh the risks versus the benefits. Lower BMI and early virological response are factors associated with improved treatment outcome. Proposed decrease of ribavirin dose due to anemia may cause relapse after ETR (end of treatment response). Despite improvements over PEG-IFN/RBV therapy, a more efficient and safer treatment option is urgently needed. Disclosure - Dr. Sornmayura - Speaking and Teaching: Merck Dr. Schiff - Consultant: Gilead, Merck; Scientific Advisory Board: Bristol Myers Squibb, Gilead, Vertex Pharmaceuticals; Grant/Research Support: Abbott, Anadys, Bristol Myers Squibb, Gilead, Merck, Medtronics, Novelos Therapetics, Orasure Technologies, Roche Molecular, Vertex Pharmaceuticals, Discovery Life Sciences, Beckman Coulter.Figure