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Ribavirin Dose Reduction: 3 Reports; Boceprevir; Abbvie All-Oral IFN-free Regimen; Telaprevir
 
 
  IAS: SAFETY OF RIBAVIRIN-CONTAINING REGIMENS OF ABT-450/r, ABT-333, AND ABT-267 FOR THE TREATMENT OF HCV GENOTYPE 1 INFECTION AND EFFICACY IN SUBJECTS WITH RIBAVIRIN DOSE REDUCTIONS - (07/03/13)
 
IMPACT OF ANEMIA AND RIBAVIRIN DOSE REDUCTION ON SVR TO A TELAPREVIR-BASED REGIMEN IN PATIENTS WITH HCV GENOTYPE 1 AND PRIOR PEGINTERFERON/RIBAVIRIN TREATMENT FAILURE IN THE PHASE 3 REALIZE STUDY http://www.natap.org/2012/APASL/APASL_08.htm
 
Timing and Magnitude of Ribavirin Dose Reduction do not impact SVR with Boceprevir + Peginterferon / Ribavirin in the Anemia Management Study in HCV G1 Patients http://www.natap.org/2012/AASLD/AASLD_35.htm
 
Article in Press
 
Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients with Chronic HCV Genotype 1 Infection-a Randomized Trial Gastroenterology August 2013
 
Fred Poordad1, Eric Lawitz1, K. Rajender Reddy2, Nezam H. Afdhal3, Christophe Hezode4,Stefan Zeuzem5, Samuel S. Lee6, Jose Luis Calleja7, Robert S. Brown, Jr8, Antonio Craxi9, Heiner Wedemeyer10, Lisa Nyberg11, David Nelson12, Lorenzo Rossaro13, Luis Balart14, Timothy Morgan15, Bruce R. Bacon16, Steven L. Flamm17, Kris V. Kowdley18, Weiping Deng19, Kenneth J. Koury19, Lisa D. Pedicone19*, Frank J. Dutko19, Margaret H. Burroughs19, Katia Alves19, Janice Wahl19, Clifford A. Brass19*, Janice K. Albrecht19*, and Mark S. Sulkowski20, for the investigators
 
1Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, USA; 2Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA; 3Beth Israel Deaconess Medical Center, Boston, MA, USA; 4Assistance Publique-Hopitaux de Paris, Henri Mondor Hospital, University of Paris-Est, Creteil, France; 5JW Goethe University Hospital, Frankfurt, Germany; 6University of Calgary, Calgary, Canada; 7Hospital U. Puerta de Hierro, Madrid, Spain; 8Columbia University College of Physicians & Surgeons, New York Presbyterian Hospital, New York, NY, USA; 9University of Palermo, Palermo, Italy; 10Hannover Medical School, Hannover, Germany; 11Kaiser Permanente Medical Center, San Diego, CA, USA; 12University of Florida, Gainesville, FL, USA; 13University of California Davis, Sacramento, CA, USA; 14 Tulane University Medical Center, New Orleans, LA, USA; 15VA Long Beach Healthcare, Long Beach, CA, USA; 16Saint Louis University School of Medicine, St. Louis, MO, USA; 17Northwestern Feinberg School of Medicine, Chicago, IL, USA; 18Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA; 19Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA; 20Johns Hopkins University School of Medicine, Baltimore, MD, USA * Former employee of Merck, Sharp, & Dohme Corp., Whitehouse Station, NJ, USA
 
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.
 
Introduction
 
Anemia is a well-established adverse event with both pegylated interferon alfa (peginterferon) and ribavirin in the treatment of chronic hepatitis C virus (HCV), particularly when these compounds are used in combination.1-3 The mechanism of anemia with ribavirin is hemolysis-associated, peg interferon 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, ribavirin exposure, body mass and degree of liver fibrosis. Roughly 30% of patients in the large phase 3 clinical trials of peginterferon/ribavirin experienced hemoglobin declines below 10 g/dL4, 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/ribavirin therapy was the dose reduction scheme for ribavirin because data supported the concept that a minimum of 60-80% of intended ribavirin 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 ribavirin dosing and that higher doses of ribavirin were more effective led many to speculate that ribavirin dosing should be maintained at all cost. This led to the use of erythropoietin and blood transfusions to support anemic patients on therapy to allow for minimal and brief reductions in ribavirin dosing.
 
The contribution of erythropoietin 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 erythropoietin had similar SVR rates to those patients who were given the growth factor.14 Given the high cost of erythropoietin and potential safety concerns with its off label use with HCV treatment-induced anemia, there remains a need to assess the utility of erythropoietin vs. ribavirin dose reduction as the primary anemia management intervention with current HCV therapy.
 
This study was designed to determine the relative efficacy and safety of ribavirin dose reduction vs. erythropoietin as the primary anemia management strategy among previously-untreated patients with chronic HCV genotype-1 infection who were treated with boceprevir plus peginterferon/ribavirin.
 
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 two arms (ribavirin dose reduction and erythropoietin 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 ribavirin dose reduction and erythropoietin arms (Figure 2A). SVR rates were similar for the ribavirin dose reduction (178/249; 71.5%) and erythropoietin arm (178/251; 70.9%; stratum-adjusted difference: -0.7% (-8.6, 7.2). In the treated/not randomized group, the SVR rate was 75/187 (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/ribavirin. If only the treated/not randomized patients who completed treatment were considered, the SVR rate was 89% (57/64). If all treated patients (including randomized and non-randomized patients) were combined, the overall SVR rate of 63% (431/687) was consistent with the overall SVR rate observed in the combined boceprevir arms of SPRINT-2, the pivotal Phase III 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 to 56% for patients with detectable HCV RNA at the start of primary anemia management (Figure 2B). A 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 S1).
 
Most patients (approximately 36% [178/500]) developed anemia (or anemia was imminent) at >4-8 weeks after starting treatment with peginterferon/ribavirin (i.e., 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 S1). 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 dose reduction arm compared to the EPO arm. However, the rate of discontinuation due to anemia was 2% in both the RBV dose reduction arm (5/249) and the EPO arm (6/251). A multivariate logistic regression analysis showed that baseline hemoglobin level, normal inosine triphosphate pyrophosphatase (ITPA) activity, age (>40 yrs) and fibrosis level (METAVIR F3/F4) were predictors of anemia (Table 2).
 
SVR rates were similar regardless of when patients began ribavirin dose reduction (Supplementary Table S2). SVR rates according to time of first ribavirin dose reduction were <4 weeks: 70% (38/54); >4-8 weeks: 64% (58/90); >8-12 weeks: 79% (49/62); >12-16 weeks: 82% (18/22); and >16 weeks: 71% (15/21). SVR rates were also similar regardless of when patients began erythropoietin: <4 weeks: 71% (39/55); >4-8 weeks: 68% (60/88); >8-12 weeks: 70% (47/67); >12-16 weeks: 88% (15/17); and >16 weeks: 71% (17/24)]. 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 ribavirin dose reduction (88% [65/74] for ≤8 weeks and 90% [60/67] for >8 weeks) or use of erythropoietin (82% [70/85] for ≤8 weeks, 85% [50/59] 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 to patients who were HCV RNA undetectable at week 8, regardless of the start of anemia management (Supplementary Table S3).
 
In the majority of patients (88% [218/249]) in the ribavirin dose reduction arm, the lowest ribavirin dose received for at least 14 days was 400-1,000 mg/d (Figure 3A); SVR rates were 73% (159/218). Notably, among patients in the ribavirin dose reduction arm who received a lowest ribavirin dose of 400 mg/d, 70% (28/40) achieved SVR. In the erythropoietin arm, for the majority of patients (72% [181/251]), the lowest ribavirin dose received for at least 14 days was 800-1,200 mg/d; SVR rates were 71% (128/181) (Supplementary Table S4).
 
SVR rates were similar between patients in the ribavirin dose reduction arm who had 1 step of ribavirin dose reduction or as many as 7 (Figure 3B and Supplementary Table S5). Approximately half (128/249) of the patients in the ribavirin dose reduction arm had 1 or 2 steps of ribavirin dose reductions. The percentage of total ribavirin dose assigned by the protocol and received by patients impacted SVR rates. In the overall population, patients receiving <50% of the assigned total ribavirin dose had a significantly lower SVR rate (P<0.0001) compared to the other groups (Figure 3C). Approximately 44% of patients (109/249) in the ribavirin dose reduction arm received at least 80% of the assigned treatment duration and received at least 80% of the total ribavirin dose assigned by the protocol, and the SVR rate in this group of patients was 92% (100/109) (Figure 3D and Supplementary Table S6). Among patients in the ribavirin dose reduction arm who received 80% of the assigned treatment duration, there was a statistically significant trend (one-sided p-value = 0.007) for lower SVR rates with receiving lower percentages of the total ribavirin dose assigned by the protocol.
 
Eighteen percent (45/249) of patients assigned to ribavirin dose reduction and 37% (93/251) of patients assigned to erythropoietin received secondary anemia management interventions. In the RBV dose reduction arm, 71% (32/45) of patients had minimum hemoglobin levels ≤8.5 g/dL at the time of secondary intervention compared to 16% (15/93) of patients in the EPO arm. The percentage of patients who received secondary interventions may 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 may continue to decline which may have led investigators to dose reduce RBV. In the EPO arm, the SVR rate in patients receiving only primary anemia management was 68% (107/158) compared to 76% (71/93) in patients also receiving secondary interventions for anemia (difference between SVR rates = 9% [95% CI=-3, 20%; p=0.146]). In the ribavirin dose reduction arm, the SVR rate in patients receiving only primary anemia management was 69% (141/204) compared to 82% (37/45) in patients also receiving secondary interventions for anemia (difference between SVR rates = 13% [95% CI=0.3, 26%; p=0.078]). Although there is a nonsignificant trend for higher SVR rates in patients who received secondary interventions compared to 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. The mean duration of EPO use was 145 days in the EPO arm as a primary anemia intervention and 153 days in the RBV dose reduction arm as a secondary anemia intervention.
 
Of patients with available biopsy results, 9% (60/664) were cirrhotic. Baseline characteristics were generally similar between cirrhotics and non-cirrhotics, but cirrhotics were more likely to be male, older, have lower baseline platelets and a higher body mass index (Supplementary Table S7). Mean baseline hemoglobin levels were 14.0 and 14.2 g/dL in cirrhotics and non-cirrhotics, respectively. The median durations of treatment were similar in cirrhotics (237 days) and non-cirrhotics (235 days). Eighty percent (48/60) of cirrhotics and 73% (438/604) of non-cirrhotics met the protocol definition for anemia and were randomized to ribavirin dose reduction or erythropoietin, respectively. There was no statistical difference between the SVR rates in cirrhotic patients who received EPO (16/25; 64% [95% CI=43, 82]) compared to cirrhotic patients who reduced the RBV dose (13/23; 57% [95% CI=34, 77]. The difference between the SVR rates in cirrhotic patients who received EPO versus RBV dose reduction was 7% (95% CI=-20, 35; p=0.60). If one pools patients with bridging fibrosis (F3) and cirrhosis (F4), there was no statistical difference between the SVR rates in F3 & F4 patients who received EPO (26/39; 67% [95% CI=50, 81]) compared to F3 & F4 patients who reduced the RBV dose (19/33; 58% [95% CI=39, 75]. The difference between the SVR rates in F3 & F4 patients who received EPO versus RBV dose reduction was 9% (95% CI=-13, 32; p=0.43). SVR rates for non-cirrhotics were 73% (162/221; 95% confidence interval=67, 79) for ribavirin dose reduction and 72% (157/217; 95% confidence interval=66, 78) for erythropoietin.
 
Cirrhotics were more likely to require secondary intervention (44% [21/48]) compared to non-cirrhotics (26% [114/438]) regardless of initial anemia management (p=0.009). In the RBV dose reduction arm, 86% (6/7) of cirrhotic patients had minimum hemoglobin levels ≤8.5 g/dL at the time of secondary intervention compared to 29% (4/14) of cirrhotic patients in the EPO arm. The rates of anemia and transfusions were similar in cirrhotics and non-cirrhotics. The rates of serious adverse events, neutropenia and thrombocytopenia were higher in cirrhotics compared to non-cirrhotics (Supplementary Table S7).
 
Safety
 
There was no difference in the frequencies of common adverse events in the ribavirin dose reduction arm vs. the erythropoietin arm (Table 3). Anemia, fatigue, nausea and headache were the most common. Serious adverse events were observed in 16% (39/249) of patients in the ribavirin dose reduction arm and 13% (33/251) in the erythropoietin arm. There was one death in the ribavirin dose reduction arm (sudden cardiac death 3 weeks after completion of treatment) and none in the erythropoietin arm. There were 27 (11%) discontinuations due to an adverse event in the ribavirin dose reduction arm compared to 32 (13%) in the erythropoietin arm. There were 10 transfusions (4%) in the ribavirin dose reduction arm compared to 5 (2%) in the erythropoietin arm. Eleven thromboembolic adverse events (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% (9/295) of patients who received erythropoietin either as a primary or secondary intervention compared to 0.3% (1 pulmonary embolism/392) of patients who did not receive erythropoietin. Of the nine patients who experienced thromboembolic events, two patients were cirrhotic at baseline and seven patients were non-cirrhotic. The median and range of erythropoietin use in these 9 patients was 199 days (range=62-288 days). One of the patients who received erythropoietin 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 4 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/ribavirin, 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 patient. The primary intervention for managing anemia should be dose reduction of ribavirin. However, if hemoglobin levels stay low (<10 g/dL), secondary interventions such as the administration of EPO, red cell transfusions, and reducing the dose of peginterferon can be considered. After the hemoglobin level is greater than 10 g/dL, the dose of ribavirin should be escalated in a stepwise fashion to a dose less than the starting dose. It is important that the patient receives at least 50% of the total mg of ribavirin calculated from the initial ribavirin dose (mg/d) and the assigned duration defined by response-guided therapy algorithm (28, 36 or 48 weeks).
 
Discussion
 
This randomized clinical trial compared ribavirin dose reduction to the use of erythropoietin for the primary management of anemia with boceprevir-based therapy. Prior randomized clinical trials of erythropoietin and peginterferon/ribavirin examined the use of erythropoietin vs. placebo in maintaining the dose of ribavirin 15,16 and improving quality of life.16 In this study, ribavirin dose reduction and erythropoietin use were comparably effective strategies in managing anemia. SVR and relapse rates were similar with ribavirin dose reduction or erythropoietin 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 erythropoietin 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 ribavirin dose reduction or the use of erythropoietin or the lowest dose of ribavirin received for a minimum of 14 days over the range of 400-1,000 mg/d. However, there was a significant trend towards a lower SVR rate in patients who received lower total doses of ribavirin 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 doses of ribavirin of 400-1,000 mg/d compared to starting doses of 600-1,400 mg/d.17 These results indicate that the initial ribavirin dose is important, but modest ribavirin dose reductions once anemia has developed do not appear to impair the likelihood of achieving an SVR in previously-untreated patients. This may be due to the long pharmacokinetic half-life in patients of approximately 298 hours for ribavirin.18
 
As expected, SVR rates were higher if patients were HCV RNA undetectable at the start of primary anemia management compared to those who were HCV RNA detectable. This was observed in both ribavirin dose reduction and erythropoietin 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 ribavirin dose reduction and with the use of erythropoietin. Hence, there is no rationale to using erythropoietin or blood transfusions to avoid ribavirin dose reduction until patients are no longer viremic, as has been the generally held belief.
 
SVR rates were similar in cirrhotic patients in the ribavirin dose reduction arm compared to the erythropoietin arm. The rates of transfusions and discontinuations due to adverse events were similar in cirrhotic patients compared to non-cirrhotic 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 to non-cirrhotic patients. These results suggest that anemia in previously untreated well-compensated cirrhotic patients can be managed in a similar manner as non-cirrhotic patients, but a higher likelihood of failure of this single mode of anemia management should be expected. The overall safety in the ribavirin dose reduction arm was similar to that in the erythropoietin arm. However, one concern with the use of erythropoietin 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 erythropoietin as a primary or secondary intervention for anemia experienced a rate of 3.1% (9/295) of thromboembolic adverse events compared to 0.3% in patients who did not receive erythropoietin. 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 erythropoietin in either the ribavirin dose reduction arm (secondary intervention) or in the erythropoietin 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 4. The algorithm differs between patients treated with boceprevir/peginterferon/ribavirin who have or do not have advanced fibrosis or cirrhosis. Because ribavirin may still be a part of most future HCV regimens including some all oral regimens in the future, this algorithm on the management of anemia may 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/ribavirin for genotypes 2 & 3, telaprevir/peginterferon/ribavirin or potential interferon-free regimens. However, these results would most likely be applicable to all ribavirin- and peginterferon/ribavirin-based regimens for HCV. Finally, many of the subgroup analyses such as the lowest ribavirin dose received for 14 days, the number of steps of ribavirin dose reductions and the comparison of cirrhotic and non-cirrhotic patients, were retrospective analyses and the numbers of patients in the subgroups is small. Because patients were not randomized into these subgroups, there may 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.
 
In summary, the results of this randomized clinical trial suggest that ribavirin dose reduction should be the primary approach to the management of anemia during treatment with boceprevir/peginterferon/ribavirin. Erythropoietin can be used as a secondary management strategy to prevent treatment interruption if ribavirin dose reduction alone is inadequate but the safety of erythropoietin use in this setting has not been clearly established.
 
 
 
 
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