Ribavirin-Induced Dysplasia.

Ribavirin is a synthetic nucleoside analogue given with pegylated interferon alfa-2a for the treatment of hepatitis C. Hemolytic anemia has been reported in 10–15% of patients, usually within 1–2 weeks of the initiation of therapy. The pathogenesis of this phenomenon is unclear. Pegylated interferon alfa-2a has been associated with pancytopenia. We report two cases of ribavirin-induced anemia that are not due solely to hemolysis.

Case A is a 56 year old African-American man, status post liver transplant in July 2005 for hepatitis C. He had a recurrence in February 2006, and was placed on ribavirin 1200 mg daily and pegylated interferon 1.8 micrograms weekly. Within 1 month, his hemoglobin dropped to 8.1 g/dL, his MCV was 107mm³ and his reticulocyte count was 57K per mm³, while maintaining a normal white blood cell and platelet count. His Coombs test was negative. There was no response to the administration of erythropoietin. Bone marrow aspirate and biopsy showed marked erythroid dysplasia - including multi-nucleated precursors and megaloblastosis. There was no morphological evidence of myeloid or megakaryocytic dysplasia. Cytogenetic studies revealed a normal male karyotype (46XY).

Case B is a 58 year old African-American man with hepatitis C. In January 2006 he was started on ribavirin 1200 mg daily, in combination with pegylated interferon. Eight weeks later, he was found to have a hemoglobin of 8.1 g/dl - decreased from 12.2 g/dL. The MCV was 104.4 mm³, and the reticulocyte count was 56K per mm³. His Coombs test was negative. Bone marrow biopsy performed at that time showed similar findings to Case A. Ribavirin and pegylated interferon were discontinued; a repeat bone marrow after six weeks showed only minimal dyserythropoiesis. He is currently maintaining his hemoglobin between 12 and 13 g/dL, with no transfusion or erythropoietin support.

There are no reported associations between ribavirin and erythroid dysplasia in humans. Ribavirin has been shown to have cytotoxic effects on bone marrows in animal models. In one study, ribavirin was given intraperitoneally to rats in doses ranging from 10 to 200 mg/kg ¹. Bone marrow samples obtained at 24 and 48 hours demonstrated micronuclei in erythroid precursors, with recovery at 72 hours. Rhesus monkeys given ribavirin at doses of 30 or 100 mg/kg/day intramuscularly for 10 days developed a normocytic, normochromic anemia, which was severe in the high-dose group ². The bone marrows demonstrated a marked decrease in late erythroid precursors, while the early precursors remained unchanged. There was also vacuolization of the erythroid precursors as well as erythrophagocytosis. No changes were noted in the myeloid precursor cells, and the megakaryocytes appeared increased. After discontinuation of treatment the hemoglobin returned to normal, demonstrating a reversible effect.

The bone marrows of the patients demonstrate ineffective erythropoiesis with marked erythroid dysplasia and megaloblastosis. These findings are associated with a decreased proportion of cells in the DNA synthesis of the cell cycle, an increase in the fraction of late precursor cells undergoing apoptosis, and an interruption in mitosis. These findings may be due to ribavirin’s interference in the maturation of erythroid cells. These observations need to be confirmed in a prospective manner in a large cohort of patients; they also suggest the need for a more complete evaluation of anemia in patients treated with ribavirin.