The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.
In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.
Dr. Fred Poordad
"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "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," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).
The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.
The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.
The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.
The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.
Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.
The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "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 the response-guided therapy algorithm, they added.
The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.
The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.
