Hemolytic Anemia and the Treatment of Chronic Hepatitis C

The treatment of chronic hepatitis C virus (HCV) has continued to evolve in the decade since the first large-scale studies of interferon alpha monotherapy were reported.1,2 Interferon alpha therapy for chronic HCV, however, continues to be limited by a low overall efficacy rate. Even with extension of treatment to 1 year, the virologic sustained response is only 20% and side effects are frequent.3,4 The most recent addition to the management of chronic HCV has been the combination of ribavirin with interferon alpha. Although the sustained response has risen to 40% with this regimen, it has come at the cost of more frequent side effects, leading to a dropout rate of 20% compared with 13% in patients treated with interferon alpha monotherapy.5,6 A particular toxicity associated with ribavirin therapy is hemolytic anemia.7 In addition, teratogenicity has been reported in animal studies.8 The mean drop of hemoglobin in patients treated with combination interferon alpha/ribavirin therapy is between 2 and 3 g/dl,5,6,9 although a fall of more than 4 g/dl occurs in about 10% of patients.5,9 Despite the risk of hemolysis, clinically significant events related to anemia have been uncommon in controlled clinical trials. However, the anemia may be poorly tolerated in patients with ischemic heart disease, particularly as treatment is extended to older patients. A report in this issue suggests hemolytic anemia is not unique to ribavirin therapy for the management of chronic HCV.10 In the patient described, the hemoglobin dropped to 6.7 g/dl within 3 months of starting interferon therapy. A decreased haptoglobin level, reticulocytosis, and increased indirect bilirubin level supported the diagnosis of hemolysis. The hemoglobin returned to normal after cessation of therapy and has remained normal during 3 years of follow-up. The patient had a diagnosis of chronic HCV with some additional autoimmune features, as noted by the presence of antinuclear antibodies (1:60), anti-liver-kidney microsomes (anti-LKM, 1:160 to 640), and rheumatoid factor (123 IU/ml). HCV RNA by polymerase chain reaction was measurable. A pretreatment biopsy suggested the predominant clinical features to be viral and not autoimmune hepatitis. Hemolysis developed in association with a marked increase of anti-LKM titers during interferon therapy, suggesting an autoimmune nature of hemolysis. The development of mild and clinically insignificant anemia is not uncommon in patients receiving interferon alpha monotherapy. If anemia is more profound, it should not be presumed to be due to a myelosuppressive effect, and evidence of hemolysis should be sought. Although this particular side effect of interferon alpha therapy is clearly uncommon, it does highlight the need to balance the risk of side effects with possible benefits in educating patients with chronic HCV about the role of interferon either as monotherapy or in combination with ribavirin to treat their disease. Sammy Saab, M.D. Paul Martin, M.D.