BOSTON — Erythropoietin is quickly becoming an integral part of hepatitis C treatment regimens, despite a lack of firm data supporting its long-term clinical benefit, Dr. Eric Yoshida said at the annual meeting of the American Association for the Study of Liver Diseases.

Only a few studies have prospectively examined the effect of erythropoietin in these patients, and whereas the studies have shown statistically significant improvements in terms of increasing hemoglobin levels and allowing for maintenance of ribavirin dosage, opinions vary on whether these differences translate into clinical benefit.

“Does this mean there is no place for erythropoietin for these patients? No, I don't think so. I think what it means is that we should treat the patient—not the numbers,” said Dr. Yoshida, head of gastroenterology at the University of British Columbia, Vancouver.

Ribavirin, considered a mainstay of antiviral therapy for hepatitis patients, can cause a dose-dependent hemolytic anemia.

Guidelines suggest decreasing the dosage of ribavirin when hemoglobin levels fall below 12 g/dL, and discontinuing the drug if levels fall below 8.5 g/dL.

But because ribavirin is so important to sustained viral response, some patients persist with their ribavirin even when they develop an anemia that significantly impairs their quality of life, Dr. Yoshida said.

He reviewed three studies that have examined the effect of erythropoietin in hepatitis C patients.

The first study, a 2003 placebo-controlled trial, randomized 64 patients to either standard of care (placebo) or weekly erythropoietin injections for 16 weeks. At baseline, the mean hemoglobin level was 11 g/dL in both groups (Am. J. Gastroenterol. 2003;98:2491–9).

At the study's end, patients receiving erythropoietin had significantly higher mean hemoglobin levels (14 g/dL versus 11 g/dL). Additionally, ribavirin dosage was similar in both groups, indicating that those taking the study drug were able to maintain their ribavirin dosage.

By the end of the trial, undetectable HCV RNA was seen in 69% of erythropoietin-treated patients and 60% of placebo patients. However, Dr. Yoshida pointed out, there was an unexpectedly high dropout rate (42% of erythropoietin patients and 50% of placebo patients). The dropout rate makes it difficult to conclude that the difference in percentage of patients with undetectable HCV RNA was related to erythropoietin therapy.

A second study, published in 2004, randomized 185 patients to placebo or erythropoietin for 8 weeks. After 8 weeks, eligible patients from both groups entered into an 8-week open-label trial (Gastroenterology 2004;126:1302–11).

By the end of the first 8 weeks, significantly more erythropoietin-treated patients than placebo patients were still taking their baseline ribavirin dose (88% versus 60%, respectively). At the end of the crossover phase, prior placebo patients had increased their ribavirin dosage significantly, from a mean of 852 mg/day to a mean of 921 mg/day.

Baseline hemoglobin levels (11 g/dL in both groups) rose to 13 g/dL in the erythropoietin group by the end of the first 8 weeks, but remained unchanged in the placebo group.

By the end of the open-label phase, mean hemoglobin levels in prior placebo patients were the same as those in patients who had taken erythropoietin for the entire study (13 g/dL).

A post hoc analysis concluded that erythropoietin-treated patients also reported significant improvements in their quality of life (Hepatology 2004;40:1450–8). The importance of quality-of-life benefits should not be underestimated in hepatitis patients, Dr. Yoshida said, because quality-of-life scores of HCV patients on treatment can be lower than those of patients with diabetes and heart failure.

The study did not find significant differences between groups in HCV RNA levels.

These trials raise yet more questions, Dr. Yoshida said. The hemoglobin level that should trigger erythropoietin treatment is still unclear. “Should the availability of erythropoietin change the hemoglobin threshold, especially when improved undetectable HCV RNA, sustained viral response, and survival have not been documented with its use?” Others might argue that starting the drug when patients have higher hemoglobin levels that are just starting to slide would be beneficial, he said.

There are also no firm data on the duration of erythropoietin treatment that is beneficial, and the studies performed to date offer little guidance.

The drug is expensive as well, adding almost $16,500 per year to the cost of treatment for hepatitis C, according to a cost-effectiveness study that Dr. Yoshida cited (Clin. Gastroenterol. Hepatol. 2005;3:1034–42). But that study also concluded that if a third-party payer covered $50,000 for every quality-of-life year gained with erythropoietin therapy, 86% of patients would still be treated “within budget.”

Still, noted Dr. Yoshida, the drug's expense along with its unproven survival benefit are enough to signal caution to many health care providers, especially those in countries with socialized health care systems.

“Hopefully, future trials will address these questions,” he said.

Dr. Yoshida's review was summarized in the Annals of Pharmacotherapy (2007;41:268–75).

He declared no financial interest in any hematopoietic agent.

Erythropoietin for HCV May Lack Clinical Benefit : The drug's expense along with its unproven survival benefit are enough to signal caution in many settings.