Anemia is a well-established adverse event with both

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1 GASTROENTEROLOGY 2013;145: Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection A Randomized Trial FRED POORDAD, 1 ERIC LAWITZ, 1 K. RAJENDER REDDY, 2 NEZAM H. AFDHAL, 3 CHRISTOPHE HÉZODE, 4 STEFAN ZEUZEM, 5 SAMUEL S. LEE, 6 JOSE LUIS CALLEJA, 7 ROBERT S. BROWN, JR., 8 ANTONIO CRAXI, 9 HEINER WEDEMEYER, 10 LISA NYBERG, 11 DAVID R. NELSON, 12 LORENZO ROSSARO, 13 LUIS BALART, 14 TIMOTHY R. MORGAN, 15 BRUCE R. BACON, 16 STEVEN L. FLAMM, 17 KRIS V. KOWDLEY, 18 WEIPING DENG, 19 KENNETH J. KOURY, 19 LISA D. PEDICONE, 19 FRANK J. DUTKO, 19 MARGARET H. BURROUGHS, 19 KATIA ALVES, 19 JANICE WAHL, 19 CLIFFORD A. BRASS, 19 JANICE K. ALBRECHT, 19 and MARK S. SULKOWSKI, 20 for the Protocol 6086 Investigators 1 Texas Liver Institute/University of Texas Health Science Center, San Antonio, Texas; 2 Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; 3 Beth Israel Deaconess Medical Center, Boston, Massachusetts; 4 Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, University of Paris-Est, Créteil, France; 5 JW Goethe University Hospital, Frankfurt, Germany; 6 University of Calgary, Calgary, Canada; 7 Hospital U. Puerta de Hierro, Madrid, Spain; 8 Columbia University College of Physicians & Surgeons, New York Presbyterian Hospital, New York, New York; 9 University of Palermo, Palermo, Italy; 10 Hannover Medical School, Hannover, Germany; 11 Kaiser Permanente Medical Center, San Diego, California; 12 University of Florida, Gainesville, Florida; 13 University of California Davis, Sacramento, California; 14 Tulane University Medical Center, New Orleans, Louisiana; 15 VA Long Beach Healthcare, Long Beach, California; 16 Saint Louis University School of Medicine, St Louis, Missouri; 17 Northwestern Feinberg School of Medicine, Chicago, Illinois; 18 Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington; 19 Merck & Co., Inc., Whitehouse Station, New Jersey; and 20 Johns Hopkins University School of Medicine, Baltimore, Maryland This article has an accompanying continuing medical education activity on page e14. Learning Objective: Upon completion of this quiz, successful learners will be able to interpret the data on the different anemia management strategies for hepatitis C patients. See Covering the Cover synopsis on page 917; see editorial on page 930. 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 ¼ 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 ¼ 500) were assigned to groups that were managed by ribavirin dosage reduction (n ¼ 249) or erythropoietin therapy (n ¼ 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, NCT Keywords: EPO; Erythropoiesis; DAA; Side Effect. 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 Abbreviations used in this paper: CI, confidence interval; EPO, erythropoietin; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response by the AGA Institute /$

2 1036 POORDAD ET AL GASTROENTEROLOGY Vol. 145, No. 5 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 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 mg/kg/wk; Merck Sharp & Dohme Corp.)/RBV ( 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 ¼ 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 ¼ 111) received 44 weeks of boceprevir/peginterferon/rbv. After a protocol amendment, patients in cohort 2 (n ¼ 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 log 10 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 ¼ 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 protocolspecified 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 ¼ 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 sdiscretion. 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 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, preexisting psychiatric conditions, and active or suspected malignancy. Laboratory exclusion criteria were hemoglobin <12 g/dl for females (males: <13 g/dl), neutrophils <1500/mm 3 (blacks/ African Americans: <1200/mm 3 ), and platelets <100,000/mm 3. 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

3 November 2013 RIBAVIRIN DOSE REDUCTION VS ERYTHROPOIETIN 1037 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 c 2 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. Results Baseline Characteristics Randomized patients who became anemic were approximately 50 years of age, 33% male, 77% white, 18% black, with a mean body mass index of 28 (Table 1). Approximately 68% were HCV subtype-1a and 91% had a baseline viral load of >400,000 IU/mL. Approximately 75% of patients had METAVIR F0/F1/F2, 5% F3 and 10% F4. The 2 arms (RBV dosage reduction and EPO use) were similar in all respects. Efficacy The efficacy analyses were based on the Full Analysis Set, which was defined as all 500 randomized anemic patients. End-of-treatment response and relapse rates were comparable between the RBV dosage-reduction and EPO arms (Figure 1A). SVR rates were similar for the RBV dosage reduction (178 of 249; 71.5%) and EPO arm (178 of 251; 70.9%; stratum-adjusted difference: 0.7%; 95% CI: 8.6 to 7.2). In the Treated/Not Randomized group, the SVR rate was 75 of 187 (40.1%). The Treated/Not Randomized group included a large number of patients who discontinued due to adverse events, and 31 of the 32 patients who discontinued during the 4-week lead-in with peginterferon/rbv. If only the Treated/Not Randomized patients who completed treatment were considered, the SVR rate was 89% (57 of 64). If all treated patients (including randomized and nonrandomized patients) were combined, the overall SVR rate of 63% (431 of 687) was consistent with the overall SVR rate observed in the combined boceprevir arms of SPRINT-2 (Serine Protease Inhibitor Therapy 2), the pivotal phase 3 study. Regardless of the primary anemia-management strategy, higher SVR rates (86%) were achieved in patients who were HCV RNA undetectable at the start of primary anemia management, compared with 56% for patients with detectable HCV RNA at the start of primary anemia management (Figure 1B). A Table 1. Demographic and Baseline Disease Characteristics for Patients Whose Primary Anemia Management Was Ribavirin Dose Reduction or Erythropoietin Use Ribavirin dosage Erythropoietin reduction (n ¼ 249) use (n ¼ 251) Mean age, y Male sex, n (%) 78 (31) 87 (35) Race, n (%) White 195 (78) 191 (76) Black 45 (18) 47 (19) Other a 9 (4) 13 (5) Body mass index, mean (SD) 28.5 (5.7) 27.8 (5.8) Baseline platelet count (10 9 /L), n(%) < (8) 24 (10) (92) 227 (90) Log 10 of geometric mean of baseline viral load b High baseline viral load 223 (90) 231 (92) (>400,000 IU/mL), n (%) HCV subtype, c n(%) 1a 167 (68) 168 (68) 1b 70 (28) 75 (30) 1 (other) 1 (0.4) 0 (0) 1 (missing) 9 (4) 4 (2) METAVIR fibrosis score, n (%) F0, F1, or F2 211 (85) 203 (81) F3 10 (4) 14 (6) F4 23 (9) 25 (10) Missing 5 (2) 9 (4) Baseline steatosis, n (%) 0% 81 (33) 93 (37) >0% 163 (65) 149 (59) Missing 5 (2) 9 (4) IL28B genotypes, n (%) CC 78 (32) 77 (31) CT 123 (50) 133 (54) TT 46 (19) 37 (15) Distribution of patients, n (%) United States 213 (86) 223 (89) Canada and Europe 36 (14) 28 (11) a American Indian, Alaskan Native, Asian, multiracial, Native Hawaiian, or other Pacific Islander. b Baseline is geometric mean of all virology collections during screening and before the randomization date. c HCV subtype as determined by Virco. multivariate logistic regression analysis showed that the viral response at treatment week 4, non-black race, HCV subtype 1b, and baseline platelet count were predictors of SVR (Supplementary Table 1). Most patients (approximately 36% [178 of 500]) developed anemia (or anemia was imminent) at more than 4 8 weeks after starting treatment with peginterferon/rbv (ie, after day 1). After treatment initiation, there was a rapid decline in the mean hemoglobin concentration, which began to plateau between weeks 8 and 12 (Supplementary Figure 2). In both arms, this decline was maintained to the end-of-treatment, with values returning to baseline levels at the end of follow-up. The mean hemoglobin values appear lower in the RBV dosage-reduction arm compared with the EPO arm. However, the rate of discontinuation due to anemia was

4 1038 POORDAD ET AL GASTROENTEROLOGY Vol. 145, No. 5 Table 2. Predictors of Anemia by Multivariate Logistic Regression a Predictors of anemia Effect Odds ratio 95% CI P value Baseline hemoglobin <.0001 (continuous variable) Normal ITPA activity b Age (>40 vs 40) Baseline fibrosis (3/4 vs 0/1/2) a Stepwise selected; all treated patients. b Normal inosine triphosphate pyrophosphatase (ITPA) activity ¼ cytosine at rs and adenine at rs for both haplotypes. Figure 1. End of treatment response, SVR rates, and relapse rate. End of treatment response, SVR rates, and relapse rates for the 2 anemiamanagement strategies (A) and SVR rates by HCV RNA levels at start of primary anemia management (B). If a patient had undetectable HCV RNA at 12 weeks after the end of treatment, but had missing HCV RNA values at and after 24 weeks after the end of treatment, this was considered an SVR. The stratum-adjusted difference adjusted for stratification factors and protocol cohort for the SVR values for EPO use (70.9%) vs RBV dosage reduction (71.5%) in panel A was 0.7% (95% CI: 8.6 to 7.2). 2% in both the RBV dosage-reduction arm (5 of 249) and the EPO arm (6 of 251). A multivariate logistic regression analysis showed that baseline hemoglobin level, normal inosine triphosphate pyrophosphatase activity, age (older than 40 years), and fibrosis level (METAVIR F3/F4) were predictors of anemia (Table 2). SVR rates were similar regardless of when patients began RBV dosage reduction (Supplementary Table 2). SVR rates according to time of first RBV dosage reduction were 4 weeks: 70% (38 of 54); >4 8 weeks: 64% (58 of 90); >8 12 weeks: 79% (49 of 62); >12 16 weeks: 82% (18 of 22); and >16 weeks: 71% (15 of 21). SVR rates were also similar regardless of when patients began EPO: 4 weeks: 71% (39 of 55); >4 8 weeks: 68% (60 of 88); >8 12 weeks: 70% (47 of 67); >12 16 weeks: 88% (15 of 17); and >16 weeks: 71% (17 of 24). Statistical analysis revealed no significant trends for increasing or decreasing SVR rates with the time of starting primary anemia management. SVR rates for patients with undetectable HCV RNA at week 8 were high regardless of when they started RBV dosage reduction (88% [65 of 74] for 8 weeks and 90% [60 of 67] for >8 weeks) or use of EPO (82% [70 of 85] for 8 weeks, 85% [50 of 59] for >8 weeks). Patients with detectable HCV RNA at week 8 had lower SVR rates (51% for 8 weeks and 57% 58% for >8 weeks) compared with patients who were HCV RNA undetectable at week 8, regardless of the start of anemia management (Supplementary Table 3). In the majority of patients (88% [218 of 249]) in the RBV dosage-reduction arm, the lowest RBV dosage received for at least 14 days was mg/d (Figure 2A); SVR rates were 73% (159 of 218). Notably, among patients in the RBV dosage-reduction arm who received a lowest RBV dosage of 400 mg/d, 70% (28 of 40) achieved SVR. In the EPO arm, for the majority of patients (72% [181 of 251]), the lowest RBV dosage received for at least 14 days was mg/d; SVR rates were 71% (128 of 181) (Supplementary Table 4). SVR rates were similar between patients in the RBV dosage-reduction arm who had 1 step of RBV dosage reduction or as many as 7 (Figure 2B and Supplementary Table 5). Approximately half (128 of 249) of the patients in the RBV dosage-reduction arm had 1 or 2 steps of RBV dosage reductions. The percentage of total RBV dosage assigned by the protocol and received by patients impacted SVR rates. In the overall population, patients receiving <50% of the assigned total RBV dosage had a significantly lower SVR rate (P <.0001) compared with the other groups (Figure 2C). Approximately 44% of patients (109 of 249) in the RBV dosage-reduction arm received at least 80% of the assigned treatment duration and received at least 80% of the total RBV dosage assigned by the protocol, and the SVR rate in this group of patients was 92% (100 of 109)

5 November 2013 RIBAVIRIN DOSE REDUCTION VS ERYTHROPOIETIN 1039 Figure 2. Rates of virologic responses among patients in the RBV dosage-reduction arm according to lowest RBV dosage, number of steps of RBV dosage reduction, and percent of total RBV dosage received. The SVR rates are shown for several subgroups in the RBV dosage-reduction arm. (A) The lowest RBV dosage was defined as the lowest daily dosage of RBV (mg/d) received for at least 14 days during the treatment period based on information in patient diaries. A lowest RBV dosage of 0 mg/d refers to patients who had many RBV dosage reductions and/or interrupted RBV temporarily for at least 14 days. (B) An RBV dosage-reduction step was defined as a decrease of 200 mg/d for 3 days based on information in patient diaries. (C, D) Percent of total RBV dosage received was calculated as the total milligrams of RBV actually received by the patient during the entire treatment period divided by the total milligrams of RBV assigned by the protocol for the entire treatment period. Results are shown for the overall population (C), as well as for those patients who received at least 80% of the duration of therapy assigned by the protocol (D). (Figure 2D and Supplementary Table 6). Among patients in the RBV dosage-reduction arm who received 80% of the assigned treatment duration, there was a statistically significant trend (1-sided P value ¼.007) for lower SVR rates with receiving lower percentages of the total RBV dosage assigned by the protocol. Eighteen percent (45 of 249) of patients assigned to RBV dosage reduction and 37% (93 of 251) of patients assigned to EPO received secondary anemia management interventions. In the RBV dosage-reduction arm, 71% (32 of 45) of patients had minimum hemoglobin levels 8.5 g/dl at the time of secondary intervention compared with 16% (15 of 93) of patients in the EPO arm. The percentage of patients who received secondary interventions might have been higher in the EPO arm due to the apparent lag time for EPO to work. On average, it can take 2 3 weeks for EPO to achieve an effect and during that time, hemoglobin can continue to decline, which might have led investigators to dosage reduce RBV. In the EPO arm, the SVR rate in patients receiving only primary anemia management was 68% (107 of 158) compared with 76% (71 of 93) in patients also receiving secondary interventions for anemia (difference between SVR rates ¼ 9% [95% CI: 3% to 20%; P ¼.146]). In the RBV dosagereduction arm, the SVR rate in patients receiving only primary anemia management was 69% (141 of 204) compared with 82% (37 of 45) in patients also receiving secondary interventions for anemia (difference between SVR rates ¼ 13% [95% CI: 0.3% to 26%; P ¼.078]). Although there is a nonsignificant trend for higher SVR rates in patients who received secondary interventions compared with no secondary intervention, it is not possible to conclude that there is a significant difference, perhaps due to the limited number of patients who received secondary intervention and the lack of randomization for this comparison. Mean duration of EPO use was 145 days in the EPO arm as a primary anemia intervention and 153 days in the RBV dosage-reduction arm as a secondary anemia intervention. Of patients with available biopsy results, 9% (60 of 664) were cirrhotic. Baseline characteristics were generally similar between cirrhotics and noncirrhotics, but cirrhotics were more likely to be male, older, have lower baseline platelets, and a higher body mass index (Supplementary Table 7). Mean baseline hemoglobin levels were 14.0 g/dl and 14.2 g/dl in cirrhotics and noncirrhotics, respectively. Median durations of treatment were similar in cirrhotics (237 days) and noncirrhotics (235 days). Eighty percent (48 of 60) of cirrhotics and 73% (438 of 604) of noncirrhotics met the

6 1040 POORDAD ET AL GASTROENTEROLOGY Vol. 145, No. 5 Table 3. Adverse Events by Treatment Arm and Thromboembolic Adverse Events by Erythropoietin Use Patients, n (%) Ribavirin dosage reduction (n ¼ 249) Erythropoietin use (n ¼ 251) Adverse event Treatment-related 247 (99) 248 (99) treatment-emergent adverse events Dosage modification due 174 (70) 111 (44) to adverse event Discontinuations due to 27 (11) 32 (13) adverse events Serious adverse events 39 (16) 33 (13) Death 1 (<1) 0 (0) Packed red cell 10 (4) 5 (2) transfusions Neutrophil counts during treatment phase per mm 3 71 (29) 68 (27) <500 per mm 3 31 (12) 44 (18) Common adverse events that occurred at a frequency >25% in either arm a Anemia 172 (69) 154 (61) Fatigue 172 (69) 177 (71) Nausea 125 (50) 149 (59) Headache 116 (47) 134 (53) Alopecia 95 (38) 97 (39) Dysgeusia 85 (34) 98 (39) Diarrhea 76 (31) 81 (32) Chills 72 (29) 78 (31) Neutropenia 70 (28) 81 (32) Influenza-like illness 67 (27) 66 (26) Insomnia 67 (27) 71 (28) Rash 66 (27) 59 (24) Decreased appetite 61 (24) 65 (26) Pyrexia 56 (22) 68 (27) On or after erythropoietin (n ¼ 295) No erythropoietin (n ¼ 392) Patients reporting any 9 (3.1) 1 (0.3) thromboembolic adverse event b Pulmonary embolism 1 (<1) 1 (<1) Thrombosed varicose 2(<1) 0 (0) vein Acute myocardial 1(<1) 0 (0) infarction Arterial occlusive disease 1 (<1) 0 (0) Arteriosclerosis 1 (<1) 0 (0) Cerebrovascular 1(<1) 0 (0) accident Deep vein thrombosis 1 (<1) 0 (0) Thrombophlebitis 1(<1) 0 (0) superficial Transient ischemia 1(<1) 0 (0) attack Venous thrombosis 1 (<1) 0 (0) a Incidence of treatment-emergent, treatment-related adverse event 25% in either arm. The relatedness (probable or possible) of the adverse event to the regimen was determined by the investigator. Patients could have had more than 1 adverse event. Common adverse events ranked by frequency in the ribavirin dosage-reduction arm. b Two patients had multiple events: acute myocardial infarction and arteriosclerosis; deep vein thrombosis and thrombosed varicose vein. protocol definition for anemia and were randomized to RBV dosage reduction or EPO, respectively. There was no statistical difference between the SVR rates in cirrhotic patients who received EPO (16 of 25; 64% [95% CI: 43 82]) compared with cirrhotic patients who reduced the RBV dosage (13 of 23; 57% [95% CI: 34 77]). The difference between the SVR rates in cirrhotic patients who received EPO vs RBV dosage reduction was 7% (95% CI: 20 to 35; P ¼.60). If one pools patients with bridging fibrosis (F3) and cirrhosis (F4), there was no statistical difference between the SVR rates in F3 and F4 patients who received EPO (26 of 39; 67% [95% CI: 50 81]) compared with F3 and F4 patients who reduced the RBV dosage (19 of 33; 58% [95% CI: 39 75]). The difference between the SVR rates in F3 and F4 patients who received EPO vs RBV dosage reduction was 9% (95% CI: 13 to 32; P ¼.43). SVR rates for noncirrhotics were 73% (162 of 221; 95% CI: 67 79) for RBV dosage reduction and 72% (157 of 217; 95% CI: 66 78) for EPO. Cirrhotics were more likely to require secondary intervention (44% [21 of 48]) compared with noncirrhotics (26% [114 of 438]) regardless of initial anemia management (P ¼.009). In the RBV dosage-reduction arm, 86% (6 of 7) of cirrhotic patients had minimum hemoglobin levels 8.5 g/dl at the time of secondary intervention compared with 29% (4 of 14) of cirrhotic patients in the EPO arm. The rates of anemia and transfusions were similar in cirrhotics and noncirrhotics. The rates of serious adverse events, neutropenia, and thrombocytopenia were higher in cirrhotics compared with noncirrhotics (Supplementary Table 7). Safety There was no difference in the frequencies of common adverse events in the RBV dosage-reduction arm vs the EPO arm (Table 3). Anemia, fatigue, nausea, and headache were the most common adverse events. Serious adverse events were observed in 16% (39 of 249) of patients in the RBV dosage-reduction arm and 13% (33 of 251) in the EPO arm. There was one death in the RBV dosagereduction arm (sudden cardiac death 3 weeks after completion of treatment) and none in the EPO arm. There were 27 (11%) discontinuations due to an adverse event in the RBV dosage-reduction arm compared with 32 (13%) in the EPO arm. There were 10 transfusions (4%) in the RBV dosage-reduction arm compared with 5 (2%) in the EPO arm. Eleven thromboembolic adverse events (ie, pulmonary embolism, thrombosed varicose vein, acute myocardial infarction, arterial occlusive disease, arteriosclerosis, cerebrovascular accident, deep vein thrombosis, thrombophlebitis superficial, transient ischemia attack, and venous thrombosis) were reported in 3.1% (9 of 295) of patients who received EPO either as a primary or secondary intervention compared with 0.3% (1 pulmonary embolism of 392) of patients who did not receive EPO. Of the 9 patients who experienced thromboembolic events, 2 patients were cirrhotic at baseline and 7 patients were noncirrhotic. Median of EPO use in these 9 patients

7 November 2013 RIBAVIRIN DOSE REDUCTION VS ERYTHROPOIETIN 1041 Figure 3. Algorithm for the management of boceprevir-related anemia. This algorithm reflects the data from this clinical study, data from additional clinical studies with boceprevir in a general HCV population, and the expert opinion of the authors. Risk factors for development of anemia are low baseline hemoglobin, normal inosine triphosphate pyrophosphatase activity, age (older than 40 years), and baseline fibrosis (F3 and F4) (Table 2), and these should be considered when determining the frequency of monitoring hemoglobin. Monitoring the level of hemoglobin for anemia is focused largely on the first 12 weeks of treatment because the decline in hemoglobin stabilizes around treatment week 12 (4 weeks peginterferon/ RBV þ 8 weeks boceprevir/ peginterferon/rbv) (Supplementary Figure 2). All patients should receive peginterferon (1.5 mg/kg/wk)/rbv for 4 weeks, and then add boceprevir (800 mg 3 times a day). Initial dosing with RBV is based on the patient s weight: 800 mg/d for <40 to 65 kg (in this clinical study, patients weighing kg received 600 mg/d and patients weighing kg received 800 mg/d); 1000 mg/d for kg; 1200 mg/ d for kg; 1400 mg/d for >105 kg. With patients who have advanced fibrosis or cirrhosis, hemoglobin levels should be checked very frequently for the first 8 weeks, and should be monitored closely at other time points as clinically appropriate. Frequent hemoglobin testing might be appropriate if a patient drops close to 10 g/dl. In contrast, the hemoglobin level in a patient without advanced fibrosis or cirrhosis should be checked every 2 weeks for the first 4 weeks, and should be monitored closely at other time points as clinically appropriate. For example, if the hemoglobin level in a patient without advanced fibrosis or cirrhosis drops to 10 g/dl by week 4, then weekly testing might be needed. Dose reduction of RBV should be the primary intervention for managing anemia. However, if the hemoglobin level remains <10 g/dl after RBV dosage reduction, the administration of EPO should be considered as well as reducing the dosage of peginterferon to 1.0 mg/kg/wk, especially if the reticulocyte counts are low. If RBV is permanently discontinued for management of anemia, then peginterferon alfa and boceprevir must also be discontinued. Once the hemoglobin level is >10 g/dl, the dosage of RBV should be increased in 200 mg/d steps to a dosage less than the initial dosage of RBV. However, the goal should be for the patient to receive at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration defined by the response-guided therapy algorithm (28, 36, or 48 weeks). Once the hemoglobin level is >11 g/dl, the administration of EPO should be discontinued. was 199 days (range, days). One of the patients who received EPO and experienced a transient ischemic attack at 4 weeks after end-of-treatment also exhibited mitral valve incompetence at week 28. Algorithm for Managing Anemia Figure 3 shows an algorithm for managing anemia. Because the rate of decline of hemoglobin was similar in F3 and F4 patients, the hemoglobin levels in patients with advanced fibrosis or cirrhosis should be monitored frequently (every week for the first 4 weeks of treatment with peginterferon/rbv, and every 1 2 weeks for the next 8 weeks after boceprevir is added to the regimen). Hemoglobin levels in patients without advanced fibrosis or cirrhosis can be monitored every 2 weeks during the first 4 weeks, then at an appropriate interval based on the patient. The primary intervention for managing anemia should be dosage reduction of RBV. However, if hemoglobin levels stay low (<10 g/dl), secondary interventions, such

8 1042 POORDAD ET AL GASTROENTEROLOGY Vol. 145, No. 5 as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon, can be considered. After the hemoglobin level is >10 g/dl, the dosage of RBV should be escalated in a stepwise fashion to a dosage less than the starting dosage. It is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration defined by response-guided therapy algorithm (28, 36, or 48 weeks). Discussion This randomized clinical trial compared RBV dosage reduction to the use of EPO for the primary management of anemia with boceprevir-based therapy. Earlier randomized clinical trials of EPO and peginterferon/rbv examined the use of EPO vs placebo in maintaining the dosage of RBV 15,16 and improving quality of life. 16 In this study, RBV dosage reduction and EPO use were comparably effective strategies in managing anemia. SVR and relapse rates were similar with RBV dosage reduction or EPO use, regardless of whether or not the patients were viremic at the initiation of the management. There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse. There were no overall differences in the SVR rates based on the timing of RBV dosage reduction or the use of EPO or the lowest dosage of RBV received for a minimum of 14 days over the range of 400 to 1000 mg/d. However, there was a significant trend toward a lower SVR rate in patients who received lower total dosages of RBV assigned by the protocol even with at least 80% adherence to the duration of treatment. Previous results from a phase 2 study showed that patients achieved lower SVR rates if they received lower starting dosages of RBV of mg/ d compared with starting dosages of 600 1,400 mg/d. 17 These results indicate that the initial RBV dosage is important, but modest RBV dosage reductions once anemia has developed do not appear to impair the likelihood of achieving an SVR in previously untreated patients. This might be due to the long pharmacokinetic half-life in patients of approximately 298 h for RBV. 18 As expected, SVR rates were higher if patients were HCV RNA undetectable at the start of primary anemia management compared with those who were HCV RNA detectable. This was observed in both RBV dosagereduction and EPO arms. These results suggest that achieving an SVR is more strongly associated with an early virologic response than with the strategy of anemia management. Among patients with detectable HCV RNA at the time of starting anemia management, SVR rates were also similar with RBV dosage reduction and with the use of EPO. There is no rationale to using EPO or blood transfusions to avoid RBV dosage reduction until patients are no longer viremic, as has been the generally held belief. SVR rates were similar in cirrhotic patients in the RBV dosage-reduction arm compared with the EPO arm. The rates of transfusions and discontinuations due to adverse events were similar in cirrhotic patients compared with noncirrhotic patients in each treatment arm; however, cirrhotic patients were more likely to receive secondary interventions for anemia and had higher rates of neutropenia and thrombocytopenia compared with noncirrhotic patients. These results suggest that anemia in previously untreated well-compensated cirrhotic patients can be managed in a similar manner as noncirrhotic patients, but a higher likelihood of failure of this single mode of anemia management should be expected. Overall safety in the RBV dosage-reduction arm was similar to that in the EPO arm. However, one concern with the use of EPO is the link to increased risk of serious cardiovascular events, thrombosis, tumor progression, and death in patients with cancer and end-stage renal disease. 19 In this clinical trial, patients who received EPO as a primary or secondary intervention for anemia experienced a rate of 3.1% (9 of 295) of thromboembolic adverse events compared with 0.3% in patients who did not receive EPO. Therefore, there is both a safety risk as well as a financial cost associated with the use of EPO in managing anemia. It is important to note that this study allowed the use of EPO in either the RBV dosagereduction arm (secondary intervention) or in the EPO arm (primary intervention) so this analysis is not a truly randomized comparison and it did not control for baseline factors. Based on the results of this and other clinical studies with boceprevir and the expert opinion of the authors, an algorithm for the management of anemia is suggested in Figure 3. The algorithm differs between patients treated with boceprevir/peginterferon/rbv who have or do not have advanced fibrosis or cirrhosis. BecauseRBVmightstillbeapartofmostfutureHCV regimens, including some all-oral regimens in the future, this algorithm on the management of anemia can be helpful to clinicians. A limitation of the study is the open-label design whereby participants knew which anemia-management strategy they were assigned. In addition, it is not clear if these results are applicable to other regimens for HCV, such as peginterferon/rbv for genotypes 2 and 3, telaprevir/peginterferon/rbv, or potential interferon-free regimens. However, these results would most likely be applicable to all RBV- and peginterferon/rbv-based regimens for HCV. Finally, many of the subgroup analyses, such as the lowest RBV dosage received for 14 days, the number of steps of RBV dosage reductions, and the comparison of cirrhotic and noncirrhotic patients, were retrospective analyses and the numbers of patients in the subgroups were small. Because patients were not randomized into these subgroups, there might be baseline differences that affect the results, and caution should be exercised in applying these data to a more advanced cirrhotic population or other groups not studied, such as HIV/HCV co-infected patients.

9 November 2013 RIBAVIRIN DOSE REDUCTION VS ERYTHROPOIETIN 1043 In summary, the results of this randomized clinical trial suggest that RBV dosage reduction should be the primary approach to the management of anemia during treatment with boceprevir/peginterferon/rbv. EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at dx.doi.org/ /j.gastro References 1. Tanaka H, Miyano M, Ueda H, et al. Changes in serum and red blood cell membrane lipids in patients treated with interferon ribavirin for chronic hepatitis C. Clin Exp Med 2005;5: Sulkowski MS, Wasserman R, Brooks L, et al. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepatol 2004; 11: Morello J, Rodriguez-Novoa S, Jimenez-Nacher I, et al. Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C. J Antimicrob Chemother 2008;62: McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361: Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46: Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54: EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011;55: Shiffman ML, Ghany MG, Morgan TR, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology 2007;132: McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123: Poordad F, Bacon B, Bruno S, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364: Bacon B, Gordon S, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364: Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364: Sulkowski MS, Poordad F, Manns MP, et al. Anemia during treatment with peginterferon alfa-2b/ribavirin and boceprevir: analysis from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial. Hepatology 2013;57: Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. Am J Gastroenterol 2003;98: Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126: Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010;376: Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis 1999; 19(Suppl 1): Barbera L, Thomas G. Erythropoiesis stimulating agents, thrombosis and cancer. Radiother Oncol 2010;95: Received February 22, Accepted July 30, Reprint requests Address requests for reprints to: Fred Poordad, MD, The Texas Liver Institute/University of Texas Health Science Center, Division of Gastroenterology and Nutrition (MC7878), 7703 Floyd Curl Drive, San Antonio, Texas poordad@txliver.com; fax: Acknowledgments The authors thank all the patients, health care providers, and investigators involved in the study, Seth Thompson (Merck) for statistical and programming support, and Karyn Davis (Merck) for technical support. L.D. Pedicone, C.A. Brass, and J.K. Albrecht are Former employees of Merck & Co., Inc., Whitehouse Station, NJ. Additional investigators are listed online in the Supplementary Materials. Conflicts of interest The authors disclose the following: F. Poordad has received consultancy fees from Merck, Vertex, Abbott, Gilead, Achillion, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, Novartis, and Janssen/ Tibotec; has grants/grants pending from Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, Sanofi-Aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics; and has received payment for development of educational presentations and speaker fees from Merck, Abbott, Achillion, Genentech, Vertex, Salix. and Gilead. E. Lawitz has received clinical research grants from Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, Sanofi-Aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, ZymoGenetics; and payment for lectures, including service on speakers bureaus for Merck. K. R. Reddy has received consultancy fees from Roche, Merck, Vertex, Janssen, Gilead, Abbvie, Idenix, and Bristol Myers Squibb; has grants/grants pending from Merck, Roche, Vertex, Janssen, Gilead, Abbvie, Bristol Myers Squibb; and payment for development of educational presentations from ViralEd. N. H. Afdhal has received grant support from Merck, Gilead, Vertex, GSK, Abbott, BMS, and Pharmasett. He has been a scientific advisor or consultant for Gilead, Vertex, Merck, Novartis, Tibotec, Johnson and Johnson, Medgenics, and Springbank; has stock/ stock options in Springbank and Medgenics; and is Editor of the Journal of Viral Hepatitis. C. Hézode reports membership of the French National Board and payment for lectures including service on speaker s bureaus for French National Meetings. S. Zeuzem has received consultancy fees from Abbott, Anadys, Bristol-Myers Squibb, Gilead, HGS, Merck, Novartis,

10 1044 POORDAD ET AL GASTROENTEROLOGY Vol. 145, No. 5 Pharmasset, Pfizer, Roche, Tibotec, and Vertex; and lecture honoraria/ member of speaker s bureau for Bristol-Myers Squibb, Gilead, Merck, Novartis, and Roche. S. S. Lee declares consulting for Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Janssen, Merck, Novartis, Roche, Vertex; research support from Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Merck, Roche, Novartis, Roche, Vertex; and has been a speaker for Bristol Myers Squibb, Gilead, Merck and Roche. J. L. Calleja has received consultancy fees from Gilead, Janssen, Merck, Novartis, Roche, Bristol Myers Squibb; and has received speaker fees from Gilead, Merck, and Roche. R. S. Brown has received grant/research support from Gilead, Janssen, Novartis, Salix, Schering/Merck, and Vertex; and has done speaking and teaching for Salix Pharmaceuticals, Roche/Genentech, Gilead, and Schering/Merck. A. Craxi has received financial support from Merck to conduct the clinical trial. H. Wedemeyer has received clinical research grants from Abbott, Bristol Myers Squibb, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens; has received consultancy fees from Abbott, Abvie, Biolex, Bristol Myers Squibb, Boehringer Ingelheim, Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV; has been a scientific advisor or consultant for Abbott, Abvie, Biolex, Bristol Myers Squibb, Boehringer Ingelheim, Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene; has received payment for development of educational presentations and speaker fees from Abbott, Bristol Myers Squibb, Gilead, ITS, JJ/Janssen-Cilag, Merck/ Schering-Plough, Novartis, Roche; and has received payment for lectures including service on speakers bureaus for Abbott, Bristol Myers Squibb, Gilead, ITS, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis and Roche. L. Nyberg has received research grants from Merck, Gilead, Abbott, Pharmasset, Roche/Genentech/Anadys, Vertex, Bristol-Myers- Squibb, Human Genome Sciences, and Idenix/Novartis; Speakers Bureau for Merck. D. Nelson has received clinical research grants from Merck and has grants/grants pending from Abbott, Bayer, Boehringer Ingelheim, Gilead, Janssen and Vertex. L. Rossaro has grants/grants pending from Roche, Genentech, Vertex, Merck, Novartis, Gilead, Pharmasset, and Bristol Myers Squibb; payment for lectures including service on speakers bureaus for Onyx, Salix, Vertex, Merck, Roche, and Genentech. L. Balart reports having received grant support and support for travel to meetings for the study or other purposes from Merck; and payment for lecture fees including service on speaker s bureaus from Merck, Genentech, and Bristol Myers Squibb. T. Morgan has grant/ grants pending from Bristol Myers Squibb, Merck, Roche/Genentech, Pharmasset, Gilead, and Vertex. B. R. Bacon has received consultancy fees from Gilead, Kadmon Pharmaceuticals, Valeant, Vertex, and Human Genome Sciences; has grants and grants pending from Roche, Gilead, Bristol Myers Squibb, Kadmon Pharmaceuticals, Valeant, Vertex, Human Genome Sciences, Wyeth, and Romark Laboratories; payment for lectures including service on speakers bureaus for Kadmon Pharmaceuticals, Gilead, and Merck; and served on Data and Safety Monitoring Boards for Novartis, ISIS, Vertex, and Gilead. S. L. Flamm has received grants from Merck, Vertex, Gilead, Novartis, Anadys, Achillion, Tibotec, Bristol Myers Squibb, and AbbVie; consultancy fees from Vertex, Gilead, Novartis, Bristol Myers Squibb, and AbbVie; and payment for lectures including service on speakers bureaus from Merck and Vertex. K. V. Kowdley has received a grant from Merck; has grants/grants pending from Bristol Myers Squibb, Intercept, Abbott, Gilead, Merck, Mochida, Conatus, Boehringer Ingelheim, Ikaria, Vertex, Janssen, and Beckman; has received royalties from Up-to-Date; has received payment for development of educational presentations from CME Outfitters and ViralEd, and for serving on advisory boards for Gilead, Abbott, Vertex, and Merck; and has received consultancy fees from Novartis, which were paid to his institution. W. Deng, K. J. Koury, F. J. Dutko, M. H. Burroughs, K. Alves, and J. Wahl are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ and hold stock and/or stock options. L. D. Pedicone is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ and holds stock and/or stock options and is now at Focus Medical Communications. C. A. Brass is a former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc Whitehouse Station, NJ and holds stock and/or stock options. Now at Novartis. J. K. Albrecht is a former employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ and holds stock and/or stock options. M. S. Sulkowski has received consultancy fees and has grants/grants pending from Abbott, Bristol Myers Squibb, Boehringer-Ingelheim, Gilead, Janssen, Merck, Novartis, Pfizer, and Vertex. Funding The trial was funded by Schering Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with all of the external academic investigators and members of the external data and safety monitoring board. The academic authors collected the data which were then analyzed by the sponsor. The sponsor held the data and made them available to all of the academic authors. The first draft of the manuscript was written by one academic author (F.P.) and two industry authors (F.D. and K.A.). 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 vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol. The views expressed herein are those of the authors and do not reflect the official policy or position of Merck & Co., Inc.