Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Abstract

The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection

“…Higher ITP concentrations are believed to protect against RBV induced ATP depletion and consequently anemia [13][14] by substituting for erythrocyte GTP in the biosynthesis of ATP [15]. Interestingly, in the above-mentioned study there was no association between these polymorphisms and treatment response, which would be expected based on such a mechanism.…”

Use of alveolar carbon monoxide to measure the effect of ribavirin on red blood cell survival†

“…Thus, the possibility cannot be excluded that the discrepancy between RBC survivals determined from reticulocyte percentage versus CO is explained by RBV-induced ineffective erythropoiesis that caused CO to overestimate the turnover of peripheral RBCs. This seems unlikely given that the deleterious effect of RBV on RBCs is thought to result from the accumulation of this drug in circulating erythrocytes, which causes membrane changes resulting in premature sequestration [9].…”

Adverse event management

“…Reaction at the site of injection 36-58 Fatigue 50-64 Headache 50-62 Myalgia 42-56 Fever 43-56 Chills 24-48 Alopeica 28-36 Artralgia 27-35 Irritability 24-35 Depression 21-34 Anorexia 14-32 Dermatitis 16-21 Anemia 12-22 Neutropenia 17-20 Thrombocytopenia 3-6 cell production occurs due to IFN-induced suppression of bone marrow erythroid precursors [7,8].…”

“…Those pharmacologically active forms are incapable of passing through the erythrocyte membrane, and so remain intracellularly retained at a concentration 60 times greater than that of plasma [7,8]. The accumulated phosphorylated derivates are slowly eliminated from the erythrocytes, which have a half-life of 40 days.…”