Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Abstract

Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

Strategies to reduce hepatitis C virus recurrence after liver transplantation

“…To try and counter this Granulocyte-Colony Stimulating Factor (G-CSF) and erythropoietin (EPO) analogues have been used to avoid antiviral dose reduction with the aim of maintaining a good virological response. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and RBV dose reduction, which may compromise sustained virologic response [36] . The impact of haematological growth factors on avoiding complications or improving virological response has not been clearly demonstrated.…”

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

“…In general, RBV is well tolerated, but it frequently induces dose-dependent anemia, requiring dose modifications in up to 22% of patients [5][6]. Current recommendations call for RBV dose reduction if hemoglobin (Hb) levels drop below 10 g/dl and demand treatment discontinuation at a Hb level < 8.5 g/dl, or suggest adjuvant treatment with erythropoietic growth factors [7].…”

High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection

“…5 The efficacy in humans remains to be proven and there are undesirable side effects. 6 RVFV is an enveloped, negatively stranded RNA virus composed of three RNA segments, complexed with the nucleocapsid (N) protein. Each segment is connected to an RVFV L-protein with RNA-dependent RNA polymerase activity.…”