Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Gastroenterology

A Randomized Trial

Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown, JR., Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, and Mark S. Sulkowski

Gastroenterology. 2013;145(5):1035-1044.

Abstract and Introduction

Abstract

Background & Aims Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.
Methods Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).
Results Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.
Conclusions Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Introduction

Anemia is a well-established adverse event with both pegylated interferon alfa (peginterferon) and ribavirin (RBV) in the treatment of chronic hepatitis C virus (HCV), particularly when these compounds are used in combination.^[1-3] The mechanism of anemia with RBV is hemolysis-associated, peginterferon suppresses bone marrow, and the mechanism of anemia with boceprevir is unknown. The relative contribution of each to the degree of anemia varies by patient, and depends on renal function, RBV exposure, body mass, and degree of liver fibrosis. Roughly 30% of patients in the large phase 3 clinical trials of peginterferon/RBV experienced hemoglobin declines below 10 g/dL^[4,5] and this threshold has been largely recommended in practice guidelines as defining clinically meaningful anemia and the threshold for anemia management.^[6,7]

Chief among the clinical management paradigms that had been developed based on peginterferon/RBV therapy was the dosage-reduction scheme for RBV because data supported the concept that a minimum of 60%−80% of intended RBV dosing and duration was required to achieve optimal rates of sustained virologic response (SVR).^[8,9] These various reports that probability of response was correlated with RBV dosing and that higher dosages of RBV were more effective led many to speculate that RBV dosing should be maintained at all cost. This led to the use of erythropoietin (EPO) and blood transfusions to support anemic patients on therapy to allow for minimal and brief reductions in RBV dosing.

The contribution of EPO in achieving SVR has never been formally studied in a randomized manner in HCV therapy, including its use with the newly approved protease inhibitors.^[10-13] In a phase 3 clinical trial of boceprevir in previously untreated patients with HCV genotype-1, it was noted that patients who became anemic but did not receive EPO had similar SVR rates to those patients who were given the growth factor.^[14] Given the high cost of EPO and potential safety concerns with its off-label use with HCV treatment-induced anemia, there remains a need to assess the utility of EPO vs RBV dosage reduction as the primary anemia-management intervention with current HCV therapy. This study was designed to determine the relative efficacy and safety of RBV dosage reduction vs EPO as the primary anemia management strategy among previously untreated patients with chronic HCV genotype-1 infection who were treated with boceprevir plus peginterferon/RBV.

Methods

Study Design

This randomized, multi-center, open-label clinical trial was designed to compare 2 strategies for the management of anemia (RBV dosage reduction vs EPO use) in adult patients with previously untreated chronic HCV genotype-1 infection who became anemic (hemoglobin ≤10 g/L) during therapy with boceprevir (VICTRELIS, 800 mg 3 times daily; Merck Sharp & Dohme Corp., Whitehouse Station, NJ) plus peginterferon alfa-2b (PegIntron, 1.5 μg/kg/wk; Merck Sharp & Dohme Corp.)/RBV (600−1400 mg/d, based on weight). The study was conducted between December 2009 and October 2011 in accordance with the principles of good clinical practice and was approved by the appropriate Institutional Review Boards and regulatory agencies. All patients provided written informed consent. Patients (n = 687) were enrolled into this study and received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir plus peginterferon/RBV (Supplementary Figure 1). Patients in cohort 1 (n = 111) received 44 weeks of boceprevir/peginterferon/RBV. After a protocol amendment, patients in cohort 2 (n = 576) were eligible to receive response-guided therapy due to the equivalent efficacy, which had been demonstrated in an earlier pivotal phase 3 trial (either 24 weeks of boceprevir/peginterferon/RBV if HCV RNA was undetectable at treatment week 8 and below the lower limit of quantitation [<25 IU/mL] at all subsequent time points, or 44 weeks of boceprevir/peginterferon/RBV if HCV RNA was detectable at treatment week 8 or ≥25 IU/mL at any subsequent time point). Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients (n = 500) who became anemic (hemoglobin ≤10 g/dL, or if the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11 g/dL) during the 4-week lead-in phase with peginterferon/RBV or during study treatment with boceprevir/peginterferon/RBV were randomized in a 1:1 ratio to RBV dosage reduction or EPO use for primary anemia management. The randomized treatment was stratified by time to development of anemia (≤16 vs >16 weeks after starting peginterferon/RBV) and by race (black vs non-black). Patients remained in the Treated/Not Randomized arm (n = 187) if they never met the protocol definition of anemia, discontinued treatment before randomization, or if their first hemoglobin value was ≤8.5 g/dL and treatment was continued at the investigator's discretion.

Supplementary Figure 1. Supplementary Figure 1 Study design and patient disposition. Patients (N = 1154) were assessed for eligibility. Eligible patients (n = 687) received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir (800 mg 3 times a day) plus peginterferon/RBV. The study was projected to enroll a sample size of 660 patients to be treated with boceprevir/peginterferon/RBV. Approximately 60% (400 patients) were expected to develop anemia. The precision of the 95% CI for the true difference in SVR rates between the treatments was expected to be approximately ±10%. Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients remained in the Treated/Not Randomized arm (n = 187) if their hemoglobin values remained >10 g/dL throughout the 28-week or 48-week treatment period or they discontinued treatment before randomization. Patients with hemoglobin ≤10 g/dL during the lead-in phase with peginterferon/RBV or who became anemic (hemoglobin ≤10 g/dL) during study treatment were randomized in a 1:1 ratio to RBV dosage reduction (RBV DR) or EPO use. If the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11g/dL, then the patient could be randomized to RBV dosage reduction or EPO use. Patients randomized during the lead-in period with peginterferon/RBV might have delayed initiation of boceprevir for up to 2 weeks at the discretion of the investigator if the anemia was significant.

The initial dosage reduction of RBV was 200 mg/d (or 400 mg/d if initial RBV dosage was 1400 mg/d) with a follow-up assessment at 2 weeks. If further dosage reduction of RBV was required, additional steps of RBV dosage reduction (by 200 mg/d) were performed. EPO was provided by the sponsor and was administered subcutaneously at 40,000 IU/wk. Secondary interventions for anemia (use of EPO in the RBV dosage-reduction arm; RBV dosage reduction in the EPO arm) were permitted for hemoglobin ≤8.5 g/dL. Packed red cell transfusions were allowed at the investigators' discretion. Patients were discontinued from the study if the hemoglobin level was ≤7.5 g/dL.

Selection of Patients

Eligibility criteria included no previous treatment for HCV infection, age older than 18 years, weight of 40−125 kg, HCV genotype-1, plasma HCV RNA level ≥10,000 IU/mL, hemoglobin ≤15 g/dL, and no contraindications for the use of EPO. Exclusion criteria were liver disease of cause other than HCV, decompensated liver disease, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breastfeeding, diabetes, hypertension, pre-existing psychiatric conditions, and active or suspected malignancy. Laboratory exclusion criteria were hemoglobin <12 g/dL for females (males: <13 g/dL), neutrophils <1500/mm³ (blacks/African Americans: <1200/mm³), and platelets <100,000/mm³.

Efficacy

The primary efficacy end point was SVR (undetectable plasma HCV RNA at 24 weeks after the end of treatment) for both the RBV dosage-reduction and EPO arms. Plasma HCV RNA levels were measured with the TaqMan 2.0 assay (Roche Diagnostics, Indianapolis, IN), which had a lower limit of quantification of 25 IU/mL and lower limit of detection of 9.3 IU/mL. The lower limit of detection was used for decision making at various points throughout the study.

Safety

Safety analyses were based on all patients who were treated with any study medication. The proportion of patients with dosage modification/discontinuation due to adverse events, treatment-related serious adverse events, World Health Organization grade 3/4 neutropenia, and hemoglobin <10 g/dL were summarized by treatment. An adverse event was considered common if it occurred in a frequency ≥25% in either study arm. An exploratory analysis also examined safety in cirrhotic patients.

Statistical Analysis

The primary objective was to compare the effect on SVR of the 2 anemia management strategies. Key secondary objectives were to determine the safety and tolerability of EPO use vs RBV dosage reduction and to define predictors of SVR.

For the primary efficacy comparison, a 95% confidence interval (CI) for the difference in the SVR rates between the 2 treatment arms was computed using a Mantel-Haenszel approach adjusting for stratification factors as well as protocol amendment cohort. SVR rates were summarized for various subgroups using descriptive statistics (number and percentage) and exact 95% CIs. Exploratory analyses included calculation of P values using the χ² test to compare SVR rates in some subgroups and the proportions of requiring secondary anemia intervention, and the Cochran-Armitage trend test for SVR rates by total RBV dosage. For safety analyses, adverse events were summarized using descriptive statistics (number and percentage).

All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors had access to the study data, and reviewed and approved the final manuscript. All authors vouch for the completeness and accuracy of the data and analyses, as well as the fidelity of the study to the protocol.

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Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

J Hepatol. 2013 Dec;59(6):1323-30. doi: 10.1016/j.jhep.2013.07.014. Epub 2013 Jul 15.

Romero-Gómez M, Berenguer M, Molina E, Calleja JL.

Source

UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain.

Abstract

The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Anemia, BMI, Boceprevir, EPO, Epoietin, GWAS, HCV, Hepatitis C virus, ITPA, Pegylated interferon, Protease inhibitor, Ribavirin, SNP, Telaprevir, body mass index, erythropoietin, genome-wide association study, hepatitis C virus, inosine triphosphate pyrophosphatase, sRfT, single nucleotide polymorphisms, transferrin soluble receptor

PMID: 23867320 [PubMed - in process]

Source

Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

Journal of Hepatology

Volume 59, Issue 6, Pages 1323-1330, December 2013

Manuel Romero-Gómez, Marina Berenguer, Esther Molina, José Luis Calleja

Received 6 May 2013; received in revised form 20 June 2013; accepted 8 July 2013. published online 17 July 2013.

Summary
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Abbreviations: BMI, body mass index, ITPA, inosine triphosphate pyrophosphatase, HCV, hepatitis C virus, GWAS, genome-wide association study, SNP, single nucleotide polymorphisms, sRfT, transferrin soluble receptor, EPO, erythropoietin

Keywords:Hepatitis C virus, Anemia, Boceprevir, Telaprevir, Pegylated interferon, Ribavirin, Epoietin, Protease inhibitor

Introduction

Anemia is a major complication of antiviral therapy in chronic hepatitis C. With dual therapy, and despite its negative impact on quality of life, it was a desirable effect due to its association with higher sustained viral response rates. In patients treated with triple therapy, the impact of anemia on outcome is controversial; its incidence though is significantly higher and the management in this scenario is more complex, frequently requiring ribavirin dose reduction, epoetin and, in some cases, blood transfusions, jeopardizing the final efficacy of triple therapy.

In this review, we will try to answer the questions that physicians face regarding the management of anemia among patients treated with telaprevir or boceprevir triple therapy. We highlight the most relevant aspects with regards to the incidence of anemia, its clinical course, factors implicated in its development, characterization, and management.

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Boceprevir, telaprevir linked to anemia in HCV-infected seniors

11/12/13

By: DENISE FULTON, Family Practice News Digital Network

WASHINGTON – Older patients with hepatitis C experienced more adverse events and more serious adverse events while treated with boceprevir or telaprevir, and they discontinued treatment more frequently than did their younger peers, according to data from theHCV-TARGET trial.

Dr. Andrew Aronsohn of the University of Chicago and his colleagues studied a subset of HCV-TARGET that comprised 1,100 patients who started treatment on a direct-acting antiviral agent before April 2012.

Most patients were aged younger than 65 years; 73 were older. Of those, 56 were treated with telaprevir and 17 with boceprevir, Dr. Aronsohn reported at the annual meeting of the American Association for the Study of Liver Diseases.

In the older group, the median age was 67 years; 53% were women. Three-fifths had been treated previously for their hepatitis C infection (HCV).

Seniors were more likely to have diabetes, coronary artery disease, and inferior renal function than were their younger peers, though not significantly so. The rate of cirrhosis in both younger and older patients was roughly the same, at just over 40%.

Treatment response was similar for older and younger patients for both drugs. Sustained virologic response (SVR) to boceprevir in treatment-naive patients was 67% for older patients and 57% for younger patients. For treatment experienced patients, the rates were 36% and 37%, respectively.

SVR to telaprevir in treatment-naive patients was 75% for older patients vs. 60% for younger patients. In treatment-experienced patients, SVR was 53% vs. 59%, respectively.

A greater percentage of older patients discontinued treatment early – 44% vs. 36%.

Nearly all (94%) older patients treated with boceprevir became anemic; 18%, or 3 patients, were classified as having severe anemia, requiring either hospitalization for their anemia or expedited reporting of the adverse event to the Food and Drug Administration. In comparison, 63% of younger patients became anemic, with 6% classified as severe.

In patients treated with telaprevir, 77% of older patients became anemic compared with 65% of younger patients. Anemia was classified as severe in 9% of older patients and 3% of younger ones.

"Seven baseline characteristics were association with anemia," Dr. Aronsohn said. Age was independently associated with developing anemia.

He cautioned that while viral kinetics and treatment outcomes were similar for older and younger patients, adverse events – particularly anemia – and early discontinuation pose a concern in patients aged older than 65 years.

HCV-TARGET is a consortium of more than 100 academic and community medical centers performing a longitudinal, observational study. Treatment is not standardized and is administered per the local standard of care. The investigators seek to capture clinical, adverse event, virological, and demographic data on patients treated for hepatitis C.

Dr. Aronsohn’s conflicts of interest were not available at press time. HCT-TARGET is sponsored by Vertex Pharmaceuticals, Merck, Genentech, and Kadmon Pharmaceuticals.

dfulton@frontlinemedcom.com

Source

Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients

J Hepatol. 2013 Nov;59(5):964-71. doi: 10.1016/j.jhep.2013.06.030. Epub 2013 Jul 10.

Scherzer TM, Stättermayer AF, Stauber R, Maieron A, Strasser M, Laferl H, Schwarzer R, Datz C, Rutter K, Beinhardt S, Steindl-Munda P, Hofer H, Ferenci P.

Department of Internal Medicine III, Medical University, Vienna, Austria.

Abstract

BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1.

METHODS: Hemoglobin levels at baseline (Hb0) and the decline after 4weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180μg peginterferon-alpha 2a and ribavirin [1000-1200mg/d; females: mean (95% CI) 15.8mg/kg (15.4-16.2); males 14.3 (14.1-14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.

RESULTS: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8g/dl (14.6-14.9) [mean (95%CI); females 13.7 (13.5-13.9); males 15.5; 15.3-15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8g/dl (2.6-3.0)] than in minor allele carriers [1.6 (1.4-1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7-2.2)] than in male patients [2.6 (2.4-2.8); p<0.001] and among females in premenopausal [1.5 (1.3-1.8)] than in postmenopausal patients [2.7 (2.3-3.1); p<0.001].

CONCLUSIONS: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Age, GWAS, Gender, HCV, Hepatitis C virus, ITPA, RVR, Ribavirin-induced anemia, SNP, SVR, genome-wide association study, rapid virologic response, single nucleotide polymorphism, sustained virologic response

PMID: 23850877 [PubMed - in process]

Source

 

HCV, Ribavirin, and Anemia: A New Dawn

Gastroenterology
Volume 145, Issue 5 , Pages 930-933, November 2013

Stanislas Pol

published online 23 September 2013.

See “Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic Hepatitis C Virus genotype 1 infection—a randomized trial,” by Poordad F, Lawitz E, Reddy KR, et al, on page 1035.

Since 1995, the treatment of hepatitis C virus (HCV) infection is based on the combination of twice daily weight-based dosing of ribavirin (RBV) and a weekly subcutaneous injection of pegylated interferon alfa (PR), which achieved a sustained virologic response (SVR) in ∼45% of patients with HCV genotype 1, 65% with HCV genotype 4, 70% with HCV genotype 3, and 80% with HCV genotype 2 infection.¹, ² Although it has been well understood that RBV improves the SVR rate by significantly reducing the occurrence of relapse or virologic breakthrough, the mechanism of action has remained poorly understood, but likely includes immunoregulatory effects. Unfortunately, this clinical benefit has come with a price: RBV increases the incidence of adverse events,¹, ² including clinical symptoms (eg, pruritus, cutaneous rash, neurocognitive troubles) or biochemical perturbations (primarily anemia). RBV -associated anemia is a result of intrinsic hemolysis, suggested to be a result of the accumulation of RBV metabolites within erythrocytes, and enhanced by interferon-associated bone marrow suppression inducing a reduction in anemia-induced reticulocytosis.³

RBV was first approved at a dosing of 11 mg/kg per day, but it was soon appreciated that higher doses were more effective, with the recommended dose increased to 13–15 mg/kg per day. Specifically, retrospective analyses first indicated the dose-effect of RBV irrespective of the genotype, and subsequent data indicated the negative impact of decreased RBV dosing on SVR rates.⁴, ⁵ The IDEAL study in naïve genotype 1-infected patients, which compared a 48-week course of 2 different doses of interferon alpha 2b (1 and 1.5 mg/kg per week) versus interferon alpha 2a did not demonstrate any significant difference in the SVR rates across the 3 arms,⁶ but for the first time showed a positive impact of anemia on the SVR rate.⁷ In addition, the IDEAL study helped to establish the association between genetic polymorphisms in the inosine triphosphate pyrophosphatase activity (ITPA) gene and RBV-associated anemia in chronic hepatitis C treated patients. These data established the “dogma” that optimization of HCV therapy had to include (1) weight-based dosing of RBV, (2) monitoring of ribavirinemia in suboptimal virologic situation for RBV dose adjustment to reach (yet undefined) thresholds of efficacious RBV exposure, and (3) use of erythropoietin (EPO), instead of RBV dose reduction (RDR), to manage anemia while maintaining the required antiviral potency of the PR combination.⁸, ⁹ Thus, physicians were managing anemia associated with antiviral therapies on the scientifically verified basis that maintaining high-dose RBV therapy despite anemia, to not affect negatively the SVR rate,⁸, ⁹

A better understanding of the HCV lifecycle has recently resulted in the development of several potential direct-acting antiviral drugs targeting viral proteins (NS3/4A protease inhibitors, NS5B nucleos(t)idic and non nucleos(t)idic polymerase inhibitors, NS5A inhibitors).¹⁰ Their combination with or without interferon and/or RBV has established a new era in the management of chronic HCV infections. The first step for this therapeutic revolution was the recent approval in 2011 of the first-generation HCV NS3/4A protease inhibitors boceprevir and telaprevir. Their use for genotype 1–infected patients in triple combinations with PR improved the SVR rates from 45% to nearly 75% in genotype 1–infected, treatment-naïve patients,¹¹, ¹² as well as those who previously failed conventional PR treatment.¹³, ¹⁴ Although a major breakthrough, both agents carry a high pill burden: Telaprevir and boceprevir are dosed 2–3 times daily, with 6 and 12 pills per day, respectively (in addition to the 4–7 RBV pills).¹¹, ¹², ¹³, ¹⁴ Protease inhibitors are metabolized by CYP3A4- and -3A5, thus requiring consideration of potential drug–drug interactions in patients receiving other treatments.¹⁵ They result in significantly more side effects,¹⁶ which in addition to those seen for PR, may also include severe cutaneous adverse reactions (telaprevir), anal discomfort (telaprevir), and exacerbated anemia (telaprevir and boceprevir). In the recent studies, rare cirrhosis decompensations and deaths have been reported, mainly related to bacterial infections in Child A cirrhotic patients with albumin levels <35 g/L and platelets count <100,000/mL.¹⁷

Indeed, boceprevir or telaprevir triple therapy increases the risk of anemia by ∼20% compared with PR alone: The prevalence of anemia, defined as a hemoglobin of <10 g/dL, is ∼50% with boceprevir and 40% with telaprevir; however, treatment discontinuation owing to anemia is rare.¹¹, ¹², ¹³, ¹⁴ During pivotal Phase III trials, boceprevir studies permitted use of EPO, and ∼43% of patients received at least one dose in the course of their HCV therapy.¹², ¹³ By contrast, the telaprevir studies did not permit use of EPO.¹¹, ¹⁴ Notably, retrospective analyses of these Phase III studies suggested that reducing the dose of RBV did not alter the SVR rate in treatment-naïve patients,¹⁸ in contrast with what has been reported for patients treated with PR therapy.⁷ In all studies, the use of EPO did not have a positive effect on SVR. However, in the telaprevir study, the very early dose reduction of RBV was associated with a slight decrease in SVR rate.

Poordad et al¹⁹ conducted the first prospective randomized trial to determine the impact of RDR (n = 249) versus EPO administration (n = 251) on SVR, for the first-line management of boceprevir-related anemia in genotype-1–naive patients. When hemoglobin level fell to <10 g/dL at any time during treatment, patients were randomized to RDR (200–400 mg as a first step, then a 200-mg step down in RBV dose, to the minimal dosage of 600 mg/d) versus EPO administration at an initial dose of 40,000 IU/wk). A secondary intervention was planned when primary intervention failed: EPO for the RDR arm, RDR for the EPO arm, and blood transfusions. The SVR rates were similar between the 2 groups (71.5% and 70.9%, respectively), regardless of the timing of the first intervention (including the leading phase) or the magnitude of RDR. Moreover, this result was not modified when considering the subgroup of patients that had detectable HCV-RNA at time of randomization. Additionally, only 18% of patients in the RDR arm required EPO, whereas 37% of patients in the EPO arm needed RDR: This second therapeutic intervention did not impact the SVR rate (76% compared with 68% in patients receiving only primary anemia management; P = .146). In the RDR arm, there was a nonsignificant trend (perhaps owing to the limited number of patients) suggestive of higher SVR rates in patients who received secondary interventions: 82 versus 69% (P = .078). Finally, among patients with RDR, SVR rates were lower in those who received lower percentages of the total RBV dose (P = .007), although they received >80% of the assigned treatment duration. It is noteworthy that results were similar in patients with extensive fibrosis or cirrhosis than in those with moderate fibrosis, suggesting that anemia in previously untreated, well-compensated cirrhotic patients can be managed in a manner similar to noncirrhotic patients. Based on their findings, the authors concluded that RDR can be the primary approach for managing anemia in boceprevir triple therapy regimens.

This carefully executed study should help to establish a new standard for the routine management of patients treated by triple therapy: RDR should be the first therapeutic intervention, thereby limiting the potential side effects of blood transfusions and the costly use of EPO (around €917 or $1200 monthly) or its intrinsic risks¹⁷: Thromboembolic adverse events were 10-fold more frequent in EPO treated patients (3.1%) compared with patients without EPO (0.3%; P = .003), a risk that has to be balanced in the decision of anemia management.

The helpful therapeutic algorithm of anemia management that the authors propose should be tempered in “difficult-to-treat” patients, for example, cirrhotic or HIV co-infected patients, who are more prone to develop anemia and may have lower SVR rates. Indeed, <10% of randomized patients had cirrhosis and a slight decrease in SVR rate has been previously reported in patients with severe fibrosis who had been managed using RDR strategies. Thus, taking into account the results of phase III and post-approval studies, French guidelines for the management of anemia in telaprevir- and boceprevir-treated patients have recommended the following practices²⁰: In noncirrhotic patients, RDR should be the first-line management of anemia, even when HCV-RNA is still detectable (ie, the dose of RBV can be gradually reduced by 200-mg steps to the minimal dosage of 600 mg/d); additional use of EPO must be discussed on a case-by-case basis, according to clinical symptoms, tolerance of anemia, and comorbidities, and failure of RDR to ameliorate anemia. In cirrhotic patients with detectable HCV-RNA, the RBV dose should be maintained, with management focused on use of EPO until HCV-RNA becomes undetectable. The Poordad's study suggests that we have to reconsider this last proposal in cirrhotic patients, first because, even if a secondary therapeutic intervention (RDR then EPO) should be more frequently expected, SVR seems to not be impacted by RDR, and second because we have to keep in mind safety issues, including thromboembolic adverse events.

With this recent change in management of chronic HCV (which we support as first-line management of anemia), we also become hopeful for further simplification of treatment guidelines. We know that second-wave direct-acting antiviral drugs have less hematologic toxicity and that the expected availability of interferon- and RBV-free regimens combining oral direct-acting antiviral drugs will rapidly make these recommendations obsolete. Nonetheless, vigilance regarding treatment-induced anemia is important, and may remain as part of the management plan for resource limited countries that continue to use PR as the therapeutic backbone for chronic HCV treatment.

Acknowledgments

S. Pol thanks Dr Matthew Albert for his help in the preparation of the manuscript.

References

Conflicts of interest S. Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Vertex, Gilead, Roche, MSD, Novartis, Abbott/Abbvie, Sanofi and Glaxo Smith Kline, and grants from Bristol-Myers Squibb, Gilead, Roche, and MSD.

PII: S0016-5085(13)01364-4

doi:10.1053/j.gastro.2013.09.036

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Video: Triple therapy effective in cirrhotic patients with HIV/HCV coinfection

Provided by Healio

October 22, 2013

BRUSSELS — Joop Arends, MD, PhD, an infectious disease specialist at the University Medical Center Utrecht in the Netherlands, discusses his presentation at EACS 2013 on the effect of triple therapy (telaprevir or boceprevir with pegylated interferon and ribavirin) on HIV/HCV coinfected patients with cirrhosis. In the study, triple therapy using either telaprevir or boceprevir was effective at 24 weeks, but severe anemia was common in the cohort.

Disclosures: Arends reports financial relationships with Merck and Janssen.

Source

Diabetes Mellitus and Advanced Liver Fibrosis Are Risk Factors for Severe Anemia During Telaprevir-based Triple Therapy

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

DOI: 10.1111/liv.12342

This article is protected by copyright. All rights reserved.

James F. Crismale1, Valérie Martel-Laferrière1, Kian Bichoupan1, Emily Schonfeld1, Alexis Pappas1, Christina Wyatt2, Joseph A. Odin1, Lawrence U. Liu1, Thomas D. Schiano1, Ponni V. Perumalswami1, Meena Bansal1, Douglas T. Dieterich1, Andrea D. Branch1,*

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12342

Publication History
Accepted manuscript online: 1 OCT 2013 12:35AM EST
Manuscript Accepted: 22 SEP 2013
Manuscript Revised: 14 SEP 2013
Manuscript Received: 20 MAY 2013

Keywords: hepatitis C virus; telaprevir; pegylated-interferon; ribavirin; triple therapy; anemia; diabetes mellitus

Abstract

Background

Adding telaprevir to pegylated-interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment.

Aims

We identified variables associated with severe anemia during telaprevir-based triple therapy.

Methods

An observational study was performed on 142 HCV-infected patients between June 2011 and March 2012. All subjects completed 12 weeks of telaprevir-based triple therapy or discontinued early due to anemia. Severe anemia was defined by a hemoglobin ≤8.9 g/dL; advanced fibrosis was determined by Fib-4 ≥3.25.

Results

The 47 (33%) patients who developed severe anemia were similar to those who did not in sex, race, and prior response to dual therapy, but they were more likely to have diabetes (23.4% vs. 6.3%, p<0.01), advanced fibrosis (46.8% vs. 29.5%, p=0.04), and a history of anemia during previous dual therapy (29.7% vs. 11.4%, p=0.02). Patients developing severe anemia were older (59 vs. 56 years, p=0.02), had lower baseline platelet counts (134 vs. 163 x10⁹/L, p=0.04), hemoglobin (14.0 vs. 15.0 g/dL, p<0.01), estimated glomerular filtration rate (79 vs. 90 mL/min/1.73m², p=0.03), and a higher median ribavirin/weight ratio (14.9 vs. 13.2 mg/kg, p<0.01). In multivariable logistic regression, presence of diabetes (OR=5.61, 95%CI: 1.59-19.72), Fib-4 ≥3.25 (OR=3.09, 95%CI: 1.28-7.46), higher ribavirin/weight ratio (OR=1.31 per mg/kg, 95%CI: 1.13-1.52), and lower baseline hemoglobin (OR=0.57 per g/dL, 95%CI, 0.41-0.80) were independently associated with developing severe anemia.

Conclusions

Severe anemia occurred in one-third of patients receiving telaprevir-based triple therapy. Risk was greater in patients with diabetes, advanced liver fibrosis, higher ribavirin/weight ratio and lower baseline hemoglobin.

Source

Management of anaemia and other treatment complications

Dig Liver Dis. 2013 Sep 30;45S5:S337-S342. doi: 10.1016/j.dld.2013.07.010.

Hézode C.

Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; INSERM U955, Créteil, France. Electronic address: christophe.hezode@hmn.aphp.fr.

Abstract

Antiviral treatment for hepatitis C virus infection has dramatically changed with the advent of triple therapy including telaprevir or boceprevir, which is associated with a new spectrum of adverse events. These may lead to dosage reduction and early discontinuation of therapy. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the telaprevir-based regimen. The first-line management of anaemia is ribavirin dose reductions. In cirrhotic patients, aggressive ribavirin dosage reductions, erythropoietin alpha and blood transfusions are effective in managing anaemia. Several deaths and cases of severe infections and hepatic decompensation were reported in cirrhotics treated in real-life setting. Patients with platelet count≤100,000/mm³ and serum albumin<35g/L should not be treated with triple therapy as it is related to a high risk of developing severe complications. The management of rashes, if well planned, does not require telaprevir discontinuation. However, approximately 5% of rashes were severe and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. Successful treatment can be enhanced by a strong patient support network including a multidisciplinary team.

Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: Anaemia, Hepatitis C, Protease inhibitor, Rash

PMID: 24091113 [PubMed - as supplied by publisher]

Source

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

J Hepatol. 2013 Oct;59(4):667-74. doi: 10.1016/j.jhep.2013.05.017. Epub 2013 May 23.

Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group.

Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.

Abstract

BACKGROUND & AIMS: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

METHODS: This prospective, multicenter study consisted of 292 patients (median age: 62years) infected with HCV genotype 1. All received 12weeks of TVR in combination with 24weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85g/L.

RESULTS: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135g/L (Hazard ratio [HR], 2.53; p=0.0013), estimated glomerular filtration rate <80ml/min/1.73m(2) (HR, 1.83; p=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p=0.0281).

CONCLUSIONS: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: AUROC, Anemia, CI, HCV, HR, Hb, Hepatitis C virus, ITPA, Inosine triphosohatase, PegIFN, Pegylated interferon, RBV, RVR, Ribavirin, SNP, SVR, TVR, Telaprevir, area under the receiver operating characteristic curve, confidence interval, eGFR, estimated glomerular filtration rate, hazard ratio, hemoglobin, hepatitis C virus, inosine triphosphatase, pegylated interferon, rapid virological response, ribavirin, single nucleotide polymorphism, sustained virological response, telaprevir

PMID: 23707372 [PubMed - in process]

Source

Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients with Chronic HCV Genotype 1 Infection-a Randomized Trial

Gastroenterology. 2013 Aug 4. pii: S0016-5085(13)01141-4. doi: 10.1053/j.gastro.2013.07.051. [Epub ahead of print]

Poordad F, Lawitz E, Reddy KR, Afdhal NH, Hézode C, Zeuzem S, Lee SS, Calleja JL, Brown RS Jr, Craxi A, Wedemeyer H, Nyberg L, Nelson D, Rossaro L, Balart L, Morgan T, Bacon BR, Flamm SL, Kowdley KV, Deng W, Koury KJ, Pedicone LD, Dutko FJ, Burroughs MH, Alves K, Wahl J, Brass CA, Albrecht JK, Sulkowski MS.

Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: poordad@txliver.com.

Abstract

BACKGROUND & AIMS: Treatment of Hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.

METHODS: Patients (n=687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n=500) were assigned to groups that were managed by ribavirin dose reduction (n=249) or erythropoietin therapy (n=251).

RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dose reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dose reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total mg of ribavirin assigned by the protocol had a significantly lower rate of SVR (P<.0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported, in 9 of 295 patients who received erythropoietin, compared to 1 of 392 patients who did not receive erythropoietin.

CONCLUSIONS: Reduction of ribavirin dose can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dose throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (mg) of ribavirin assigned by response-guided therapy.ClinicalTrials.gov number, NCT01023035.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID 23924660 [PubMed - as supplied by publisher]

Full text: Elsevier Science

Source

HCV treatment improves survival among anemic patients

Provided by Healio

Mohanty A. Clin Gastroenterol Hepatol. 2013;11:741-747.

June 6, 2013

While anemia increased mortality rates among patients with hepatitis C, those who underwent treatment for the infection experienced significantly improved survival in a recent study.

Researchers performed a retrospective analysis of 200,139 veterans with chronic hepatitis C, including 29,510 with anemia, as well as 195,166 controls without HCV. Patients had been enrolled in the Electronically Retrieved Cohort of Hepatitis C-Infected Veterans between 2001 and 2008. HCV treatment was initiated in 1,820 patients with and 17,755 without anemia.

Anemia was more prevalent among patients with HCV than controls (14.7% vs. 12.5%; P<.001). Multivariate analysis indicated significant associations between pretreatment anemia and decompensated liver disease (OR=3.69; 95% CI, 3.53-3.86), chronic kidney disease (OR=3.36; 95% CI, 3.23-3.51) and black race (OR=2.03; 95% CI, 1.95-2.11).

Patients with anemia were significantly less likely to initiate HCV therapy (OR=0.56; 95% CI, 0.56-0.62), with the likelihood of treatment decreasing proportionally with anemia severity (P<.001 for trend).While mortality rates were higher among anemic patients (139.2 per 1,000 person-years vs. 35.9 per 1,000 person-years among those without anemia), treated anemic participants had lower all-cause mortality rates than untreated anemic patients (54.2 per 1,000 person-years vs. 146.8 per 1,000 person-years).

Investigators calculated an adjusted HR of 0.45 (95% CI, 0.39-0.51) for HCV treatment among anemic participants after adjustment for covariates. This risk reduction was similar to that observed among participants without anemia (aHR=0.44; 95% CI, 0.41-0.48), and was not impacted by anemia severity. Sensitivity analysis excluding those with major comorbidities (n=5,925, HCV patients with anemia; n=69,478, without anemia) yielded similar results, including a greater risk reduction among treated participants (HR=0.28; 95% CI, 0.22-0.37).

“Our study shows the importance of identifying and treating individuals with chronic HCV infection who have pretreatment anemia,” the researchers concluded. “Treatment for HCV infection in anemic individuals confers a significant survival advantage after adjusting for numerous comorbidities. A better understanding of pathways that lead to baseline anemia in chronic HCV-infected individuals and targeted therapies to treat this may allow HCV treatment for a higher proportion of individuals.”

Disclosure: The researchers report numerous financial disclosures.

Source

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

Journal of Hepatology

Article in Press

Received 5 March 2013; received in revised form 19 April 2013; accepted 13 May 2013. published online 28 May 2013.
Accepted Manuscript

Eiichi Ogawa, Norihiro Furusyo, Makoto Nakamuta, Eiji Kajiwara, Hideyuki Nomura, Kazufumi Dohmen, Kazuhiro Takahashi, Takeaki Satoh, Koichi Azuma, Akira Kawano, Yuichi Tanabe, Kazuhiro Kotoh, Shinji Shimoda, Jun Hayashi The Kyushu University Liver Disease Study (KULDS) Group

Abstract

Background & aims

Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PEG-IFN) α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PEG-IFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy.

Methods

This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb) <85 g/L.

Results

101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb<135 g/L (Hazard ratio [HR], 2.53; P=0.0013), estimated glomerular filtration rate <80 mL/min/1.73m² (HR, 1.83; P=0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; P=0.0024). For patients with ITPA CC (n=227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; P=0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; P=0.0281).

Conclusions

Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Keywords: Hepatitis C virus, Anemia, Telaprevir, Inosine triphosohatase, Pegylated interferon, Ribavirin

Abbreviations: HCV, hepatitis C virus, PEG-IFN, pegylated interferon, RBV, ribavirin, SVR, sustained virological response, TVR, telaprevir, ITPA, inosine triphosphatase, SNP, single nucleotide polymorphism, Hb, hemoglobin, eGFR, estimated glomerular filtration rate, RVR, rapid virological response, HR, hazard ratio, CI, confidence interval, AUROC, area under the receiver operating characteristic curve

No full text is available. To read the body of this article, please view the PDF online

Source.

Pretreatment anemia raises mortality risk among HCV/HIV coinfected patients

Erqou S. J Viral Hep. 2013;doi:10.1111/jvh.12107.

May 8, 2013

Patients coinfected with hepatitis C and HIV are at increased risk for death with the presence of pretreatment anemia, while the initiation of therapy for HCV improves survival in this population, according to recent results.

Researchers evaluated data from 5,000 patients coinfected with hepatitis C and HIV, including 1,671 participants who had anemia before undergoing therapy during a maximum follow-up of 7 years. Data were collected from the Electronically Retrieved Cohort of Hepatitis C-Infected Veterans. All-cause mortality rates were determined and compared between those with and without pretreatment anemia, and between anemic patients who did and did not initiate HCV treatment.

Multivariate analysis indicated significant associations between pretreatment anemia and factors including advanced age (OR=2.1; 95% CI, 1.46-3.03 for every 5 years), African-American race (OR=2.11; 95% CI, 1.79-2.5) and the presence of chronic kidney disease (OR=3.34; 95% CI, 2.8-4), decompensated liver disease (OR=2.56; 95% CI, 2.18-3.01) and cancer (OR=1.64; 95% CI, 1.29-2.09).

Within the cohort, 333 nonanemic patients and 84 with anemia initiated therapy for HCV. Anemic patients were less likely than nonanemic participants to undergo therapy (OR=0.48; 95% CI, 0.37-0.61).

During follow-up, anemic patients had significantly higher mortality rates (144.2 deaths per 1,000 person-years compared with 47.5 among those without anemia), while anemic patients who initiated HCV treatment had lower rates than those who did not (66.6 per 1,000 person-years vs. 149.5). Undergoing therapy for HCV was significantly associated with an improved mortality rate (HR=0.41; 95% CI, 0.29-0.58). Adjustment for covariates, including the presence of multiple comorbidities, did not eliminate the significance of the association (HR=0.36; 95% CI, 0.21-0.62).

“Our study demonstrated that HCV treatment is associated with substantial survival benefit in HCV/HIV coinfected individuals with pretreatment anemia,” the researchers concluded. “The importance of these findings is heightened because this group of patients has significantly higher mortality and lower HCV treatment rates as compared to those without anemia. Further study is needed to find strategies … in optimizing HCV treatment to improve HCV treatment rates among this group.”

Source

Anemia Top Side Effect of HCV Antivirals

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Two years after direct-acting antiviral drugs for hepatitis C virus (HCV) infection hit the U.S. market, anemia has been far and away their most significant adverse effect, researchers said here.

Outcomes in more than 1,400 U.S. patients taking a HCV protease inhibitor in routine practice for chronic infection indicated that more than half had experienced anemia, whether they received boceprevir (Victrelis) or telaprevir (Incivek), according to Michael W. Fried, MD, of the University of North Carolina in Chapel Hill.

Triple therapy with one of these drugs plus ribavirin and pegylated interferon is now the standard of care for HCV genotype 1.

Although severe skin rashes have been telaprevir's most talked-about side effect, prompting the FDA to add a boxed warning to the drug's label, severe anemia was much more common. Of the 1,082 patients in the study taking telaprevir, 27 showed severe anemia, compared with five patients developing severe rash, Fried and colleagues found.

Among 344 patients on boceprevir, six developed severe anemia.

These data were collected by a consortium of 44 academic centers and 59 community-based clinics in the U.S., which have sought to enroll all patients receiving these drugs. The only exclusion criteria were consent refusal or participation in another study of HCV therapies.

Beyond that, clinicians were free to prescribe dosing regimens and manage adverse effects according to their own judgment.

Anemia in most patients was treated mainly by reducing ribavirin dosages, for patients with cirrhosis as well as those without (65% and 54%, respectively).

Clinicians resorted to erythropoietin-type drugs in 13% of cirrhotic patients and 19% of those with no cirrhosis. Transfusions were given to 17% and 8% of cirrhotic and noncirrhotic patients, respectively.

Baseline cirrhosis was a significant risk factor for severe anemia and premature discontinuation of treatment. Fried and colleagues found odds ratios of 1.5 to 2.2 (all P<0.05) for risk of these outcomes as well as for any serious adverse event and for early discontinuation attributed to adverse effects.

Some 11% of the 550 patients with cirrhosis developed decompensation on treatment, compared with 1% of noncirrhotic patients.

Fried and colleagues also found virologic response rates in their patients to be similar to, if not better than, those seen during the drugs' clinical trials.

Patients taking telaprevir had HCV viral loads below the limits of detection or quantitation at rates of 91% to 96% at treatment week 12, depending on prior treatment history.

Corresponding data for boceprevir patients ranged from 63% to 87%.

About one-quarter of patients in the study stopped all therapy prematurely. Lack of efficacy and adverse events accounted for 35% and 40% of discontinuations, respectively.

At a press briefing, Laurent Castera, MD, of Centre Hospitalier Universitaire de Bordeaux in France, who was not involved with the study, said it was noteworthy in representing a real-world patient population, as opposed to the carefully selected samples enrolled in clinical trials.

Despite the broader mix of patients seen in the post-marketing study, Castera said the efficacy results were "comparable" to those seen in the two drugs' registration trials. Rates of anemia and other adverse events also tracked closely with previous trial results, in which some degree of anemia occurred with both drugs in half of patients.

The study was funded by Vertex, Merck, Kadmon, and Genentech.

Fried reported relationships with Genentech, Merck, Vertex, Gilead, Bristol-Myers Squibb, and Abbott.

Castera reported relationships with Bristol-Myers Squibb, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fried M, et al "HCV-TARGET: a longitudinal, observational study of North American patients with chronic hepatitis C (HCV) treated with boceprevir or telaprevir" EASL 2013; Abstract 818.

Source

Management of Anemia in Patients Receiving Protease Inhibitors

Gastroenterology & Hepatology Volume 8, Issue 4 April 2012

Stephen A. Harrison, MD, LTC, MC
Chief of Hepatology
Brooke Army Medical Center
Clinical Associate Professor of Medicine
University of Texas Health Science Center at San Antonio
San Antonio, Texas

G&H How frequently does anemia occur in patients who are receiving protease inhibitor– based therapy?

SAH Anemia occurs frequently in these patients—certainly more frequently than it does in patients receiving only pegylated interferon and ribavirin. In a pooled analysis of the clinical safety data from trials of telaprevir (Incivek, Vertex), hemoglobin values less than 10 g/dL were found to occur in approximately 36% of patients receiving telaprevir-based triple therapy. More severe anemia, defined as hemoglobin values less than 8.5 g/dL, was observed in about 14% of patients. Among patients treated with pegylated interferon and ribavirin alone, only 17% had hemoglobin values less than 10 g/dL, and 5% had hemoglobin values less than 8.5 g/dL.

Similar rates of anemia were seen in trials of boceprevir (Victrelis, Merck). Pooled data from SPRINT-1 and SPRINT-2 showed that approximately 49% of patients had hemoglobin values less than 10 g/dL, and approximately 6% of patients had hemoglobin values less than 8.5 g/dL. Similar rates of anemia were observed in RESPOND-2, a trial that evaluated boceprevir-based triple therapy in interferon-experienced patients: Approximately 49% of these patients had hemoglobin values less than 10 g/dL, and approximately 10% of patients had hemoglobin values less than 8.5 g/dL. Among patients in the control group, who were treated with pegylated interferon and ribavirin alone, approximately 30% of patients showed a hemoglobin value less than 10 g/dL, and only approximately 3% of patients had a hemoglobin value less than 8.5 g/dL. Overall, there is a significantly higher rate of clinically significant anemia when therapy includes either boceprevir or telaprevir compared to treatment with pegylated interferon and ribavirin alone.

G&H Are rates of anemia similar between these 2 protease inhibitors?

SAH Yes, rates of anemia seem to be fairly similar with both telaprevir and boceprevir. While the pooled registration data suggest that telaprevir has higher rates of grade 3/4 anemia (hemoglobin levels <8.5 g/dL; 14% with telaprevir vs 6–10% with boceprevir), the boceprevir studies allowed the use of erythropoietin at the investigator’s discretion. While prospective, randomized, head-to-head trials assessing both frequency and severity of anemia are lacking, interim data from an ongoing French study (presented as an abstract at HepDART 2011) found on preliminary analysis that moderate, grade 2 anemia (hemoglobin level of 8–10 g/dL) occurred in 33% of telaprevir-treated patients and 31% of boceprevir-treated patients. Grade 3/4 anemia (hemoglobin level <8 g/dL) occurred in 13% of telaprevirtreated patients and 6% of boceprevir-treated patients. The transfusion rate was 18% for telaprevir-treated patients and 6% for boceprevir-treated patients. Overall, these findings correlate with clinicians’ anecdotal clinical experience, which shows significant anemia with both drugs.

G&H How frequently does anemia lead to either dose reduction or discontinuation of therapy?

SAH Dose reductions occur roughly twice as often when a protease inhibitor is added to the treatment regimen. According to the registration trial data, dose reductions occur in approximately 26% of patients treated with boceprevir.

Similarly, data from the telaprevir registration trials show that dose reductions occur in approximately 32% of patients. In terms of treatment discontinuation, data show that boceprevir-based therapy is discontinued in approximately 1% of patients, and telaprevir-based therapy is discontinued in 3–4% of patients. Again, both drugs show roughly similar rates of dose reductions and discontinuation.

G&H What are the clinical consequences of anemia?

SAH The presence of anemia does not negatively impact sustained virologic response (SVR) rates. However, it is well known that quality of life is certainly affected, which can lead to potential compliance or adherence issues. Recent data with the protease inhibitors suggest that clinicians can dose-reduce ribavirin fairly significantly in the setting of anemia and still achieve high SVR rates. Treatment discontinuation obviously has a more significant effect on clinical outcomes, but discontinuation is rare. Nonetheless, more data are needed to clearly show how quickly ribavirin dose reductions can occur (before virus negativity) and how long ribavirin can be stopped without affecting overall SVR rates. In the meantime, I advocate dose reduction instead of drug discontinuation for anemia, especially given that clinicians can probably get by with lower doses of ribavirin in the era of direct-acting antiviral drugs than they could when treating patients with pegylated interferon and ribavirin alone. If clinicians must discontinue ribavirin, they should do so for a short period of time (2–3 days) and then restart ribavirin at a lower dose.

In addition to necessitating dose reductions or discontinuations, anemia can significantly affect patients’ quality of life in terms of fatigue, inability to go to work and/or be productive at work, and difficulty in performing activities of daily living. As a result, compliance with therapy can become an issue. Thus, the effects of anemia extend beyond the possible impact on SVR rates to include compliance and quality-of-life issues as well.

G&H Have any studies compared SVR rates in patients with and without anemia?

SAH Yes. There are 2 large studies in genotype 1 hepatitis C virus (HCV)-infected patients treated with pegylated interferon and ribavirin (IDEAL, n=3,070; CHARIOT, n=871) showing that patients who developed anemia (hemoglobin level <10 g/dL) were significantly more likely to obtain SVR than those without anemia. Post–hoc, retrospective studies with telaprevir and boceprevir have also been conducted, but to date, these results remain in abstract form. Data from the REALIZE trial and combined data from ADVANCE and ILLUMINATE (with telaprevir) demonstrate that anemia is not a significant predictor of SVR. However, a retrospective review of the SPRINT-2 and RESPOND-2 trials (with boceprevir) did find a positive association with anemia and SVR.

G&H Are there any factors that predict the likelihood of anemia in patients receiving protease inhibitor–based therapy?

SAH Patients who had significant anemia during prior treatment with pegylated interferon and ribavirin and are re-treated with boceprevir- or telaprevir-based triple therapy are likely to develop anemia again, and anemia may be more severe given the addition of the protease inhibitor. Retrospective data from the telaprevir registration trials show on multivariate analysis that older age, lower body mass index, lower baseline hemoglobin level, more advanced fibrosis, and genotype 1b HCV are all significantly associated with anemia. Retrospective data from the boceprevir registration trials show on multivariate analysis that baseline hemoglobin level, gender, age greater than 40 years, statin use, and race were associated with anemia.

G&H Can clinicians address some of these factors before starting treatment?

SAH Clinicians need to do due diligence and look at the patient’s past treatment. Was there significant anemia? Are patients starting out with lower hemoglobin levels? Are they cirrhotic? Are they older? Do they have any renal impairment issues? If any of these factors are identified ahead of time, then clinicians should be quicker to dose-reduce or add an agent like erythropoietin if hemoglobin levels begin to drop.

G&H How effective is erythropoietin for the management of anemia in patients who are receiving a protease inhibitor plus pegylated interferon and ribavirin?

SAH We lack good, clear-cut data regarding the effect of erythropoietin on SVR rates in patients treated with directacting antiviral drugs. Erythropoietin was not allowed in the telaprevir registration trials. In the boceprevir registration trials, erythropoietin was allowed at the discretion of the investigator, but these studies were not designed to evaluate the effect of erythropoietin on SVR rates. The results of a recently completed prospective trial assessing the benefits of concomitant erythropoietin use for anemia in boceprevir-based therapy are anxiously awaited.

Prior to the advent of direct-acting antiviral drugs, a prospective, randomized, placebo-controlled trial showed that the use of erythropoietin for anemia related to treatment with pegylated interferon and ribavirin resulted in maintenance of the ribavirin dose, stabilization of the hemoglobin decline, and improvement in quality of life compared to ribavirin dose reduction alone.

G&H When do you consider adding erythropoietin to a patient’s treatment regimen?

SAH This decision should be made at the discretion of the individual clinician, as there are no guidelines regarding the use of erythropoietin. If a patient experiences anemia, I personally prefer to try ribavirin dose reduction of 400–600 mg as a first-line measure, depending on the initial severity of the anemia. Then, if the hemoglobin level has not stabilized, I will add erythropoietin before further dose-reducing ribavirin or withholding ribavirin. While adding erythropoietin is not my first-line treatment for anemia, it is an option if a patient’s hemoglobin level is not stabilizing. Consideration can also be given to pegylated interferon dose reduction, as this may also help anemia. Data from the previously mentioned IDEAL trial show that with conventional pegylated interferon and ribavirin therapy, dose reductions from 1.5 mcg/kg/week to 1.0 mcg/kg/week did not adversely affect SVR.

G&H In which patients is erythropoietin contraindicated?

SAH The black box warning for erythropoietin states that this drug should not be used in patients with hemoglobin values greater than 12 g/dL. Thus, clinicians should not start erythropoietin until the patient’s hemoglobin level falls below 12 g/dL, and erythropoietin should be discontinued once the hemoglobin level rises back above 12 g/dL. Caution should be used when treating patients with endstage renal disease as well. Clinicians should also be aware of the relatively rare, but significant, complication of pure red cell aplasia that has been reported with the use of recombinant erythropoietin.

G&H What further research do you hope to see in this area over the next couple of years?

SAH Telaprevir and boceprevir, both of which are now approved by the US Food and Drug Administration, are the first direct-acting antiviral agents to come onto the market. Unfortunately, these drugs are associated with significant anemia; in general, patients who are receiving either of these drugs experience an additional hemoglobin decline of approximately 1 g/dL beyond the hemoglobin decline caused by pegylated interferon and ribavirin alone. The good news is that the second-generation direct-acting antiviral agents currently in development will probably cause less anemia than the 2 drugs that are currently available.

In addition to new drugs, we need further research regarding treatment of anemia in patients receiving telaprevir or boceprevir, including studies assessing how quickly we can dose-reduce ribavirin and by how much. The use of erythropoietin for anemia and its effect on SVR should be assessed. Finally, data suggest that polymorphisms in the inosine triphosphate pyrophosphatase (ITPA) gene may help to predict ribavirin-associated anemia during antiviral treatment, and further research is needed regarding the utility of this test. Should we be testing for this gene mutation in the same way that we now test for interleukin-28B (IL-28B) mutations prior to initiating antiviral therapy? More data are needed to determine whether this information would positively impact outcomes.

G&H How might such information help clinicians prevent treatment-induced anemia?

SAH If I had information suggesting that a patient was at increased risk for anemia, then I would probably check for anemia more frequently at the start of therapy. My preferred strategy—especially in patients who I feel are at risk for developing anemia—is to obtain complete blood counts at Week 1 and Week 2. If these tests show that the patient is doing well, then I may wait until Week 4 before performing follow-up testing. However, if testing at Week 1 and Week 2 shows that the patient’s hemoglobin level has dropped significantly, then I would adjust the ribavirin dose and obtain another complete blood count at Week 3. The key for treating anemia in the setting of HCV therapy is to address anemia very quickly, because it is much harder to bring hemoglobin levels back up after they have declined than it is to mitigate the rate of decline.

The opinion or assertions contained herein are the private views of the author and are not to be construed as official or reflecting the view of the US Department of the Army or the US Department of Defense.

Suggested Reading

Alavian SM, Tabatabaei SV, Behnava B. Impact of erythropoietin on sustained virological response to peginterferon and ribavirin therapy for HCV infection: a systematic review and meta-analysis. J Viral Hepat. 2012;19:88-93.

Mac Nicholas R, Norris S. Review article: optimizing SVR and management of the haematological side effects of peginterferon/ribavirin antiviral therapy for HCV—the role of epoetin, G-CSF and novel agents. Aliment Pharmacol Ther. 2010;31:929-937.

Nishimura T, Osaki R, Shioya M, et al. Polymorphism of the inosine triphosphate pyrophosphatase gene predicts ribavirin-induced anemia in chronic hepatitis C patients. Mol Med Report. 2012;5:517-520.

Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.

Zeuzem S, Andreone P, Pol S, et al; REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.

Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

Bacon BR, Gordon SC, Lawitz E, et al; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.

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EASL 2012: Merck Reports Phase III Study Results Evaluating Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy

BARCELONA, April 19, 2012 - Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced final results from a Phase III, open-label study designed to compare the impact of two anemia management strategies on sustained virologic response (SVR)¹ in patients with chronic hepatitis C virus (HCV) genotype 1 infection treated with VICTRELIS^® (boceprevir) in combination with PEGINTRON^® (peginterferon alfa-2b) and ribavirin (P/R). The rates of SVR were 71 percent for both groups: those patients whose anemia was managed by ribavirin dose reduction (178/249) and those patients whose anemia was managed by the addition of erythropoietin (EPO) (178/251). The rates of relapse were identical at 10 percent in both groups. These results were presented today for the first time as part of a late breaker poster session [poster #1419] at The International Liver Congress^™ / 47th European Association for the Study of the Liver (EASL) annual meeting.

"Chronic hepatitis C treatment regimens with peginterferon alfa and ribavirin are commonly associated with the development of anemia, and this effect is further increased with the addition of VICTRELIS," said Fred Poordad, M.D., chief of hepatology and liver transplantation, Cedars-Sinai Medical Center, Los Angeles. "The results of this study show there was no difference in SVR rates among these anemia management strategies and that ribavirin dose reduction should be the primary strategy for managing anemia in patients taking VICTRELIS combination therapy."

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.

About the Study
In this study, 687 treatment-naïve adult patients with chronic HCV genotype 1 who had baseline hemoglobin levels of less than or equal to 15 g/dL were enrolled in a multinational, open-label trial and monitored for the development of anemia. Patients were treated with a 4-week lead-in of peginterferon alfa-2b (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (800 mg three times a day) after week 4 for 24 or 44 weeks based on HCV-RNA levels at treatment week 8. Sixteen (16) percent (111/687) of patients were enrolled in Cohort 1 and assigned a fixed-dose regimen that included the 4-week lead-in of P/R followed by the addition of VICTRELIS for 44 weeks. A protocol amendment was then added to allow the use of the response-guided therapy (RGT) paradigm, consistent with findings in the pivotal clinical studies for VICTRELIS, and the rest of the patients were enrolled in Cohort 2. The results for patients receiving the fixed-dose regimen (Cohort 1) versus the RGT paradigm (Cohort 2) did not differ and have been combined in the presentation of these data. Patients with a less than 2-log₁₀ decline in HCV-RNA at week 12, or a greater than or equal to lower limit of quantification of HCV-RNA at week 24 were considered treatment failures and were discontinued from the studies.

A total of 500 patients developed anemia, defined by having hemoglobin of less than or equal to 10 g/dL (or less than 11 g/dL and were expected to reach less than or equal to 10 g/dL before the next visit). These patients were randomized to receive either ribavirin dose reduction (by 200 to 400 mg/d) or the addition of EPO (40,000 IU/week). A secondary method of anemia management, such as the addition of EPO, ribavirin dose reduction or transfusion, was later permitted if a patient's hemoglobin reached less than or equal to 8.5 g/dL. Treatment was discontinued if hemoglobin levels reached less than or equal to 7.5 g/dL. If the initial hemoglobin measurement qualifying a patient as anemic was less than or equal to 8.5 g/dL, that patient was not randomized to one of the anemia management strategies.

The primary endpoint of the study was the comparison of SVR in patients who were randomized to receive ribavirin dose reduction or the addition of EPO.

Safety Findings
The safety profiles were similar regardless of anemia management strategy. The most common adverse events (occurring in 30 percent or more of patients in either group) were anemia, neutropenia, diarrhea, dysgeusia, nausea, chills, fatigue, headache, insomnia and alopecia. There was no difference in the incidence of adverse events between the ribavirin dose reduction and EPO treatment arms, including influenza-like symptoms (27 percent each), fatigue (70 percent vs. 71 percent), depression (20 percent vs. 21 percent), anxiety (12 percent each), shortness of breath (19 percent vs. 21 percent) and cardiovascular events (14 percent vs. 13 percent), respectively.

Serious adverse events occurred in 16 percent of patients in the ribavirin dose reduction arm and 13 percent of patients in the EPO arm. The discontinuation rates were 11 and 13 percent, due to any adverse event, and 2.0 and 2.4 percent due to anemia, respectively. There was one death in the ribavirin dose reduction arm that occurred three weeks following the end of treatment, with cause of death reported as "sudden cardiac death".

Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio^® (sildenafil) or Adcirca^® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia -- The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. If hemoglobin is less than10 g/dL, a decrease in dosage or interruption of ribavirin is recommended. If hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is recommended. Decreases in neutrophil counts also may require dose reduction or discontinuation of PR. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

In the pivotal clinical trials, the proportion of patients who experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL was higher in subjects treated with the combination of VICTRELIS plus P/R than in those treated with P/R alone, respectively.

-- Treatment-naïve patients experienced hemoglobgin levels less than 10 g/dL and less than 8.5 g/dL in 49 percent and six percent of patients treated with VICTRELIS plus P/R, compared to 29 percent and three percent of patients treated with P/R alone, respectively.

-- Patients who previously failed P/R therapy experienced levels less than 10 g/dL and less than 8.5 d/L in 49 percent and 10 percent of patients treated with VICTRELIS plus P/R, compared to 25 percent and 1 percent of patients treated with P/R alone, respectively.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2011 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

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Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

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VICTRELIS^® and PEGINTRON^® are trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

¹ SVR, the protocol specified primary efficacy endpoint of the study, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.

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