taribavirin and Anemia--Hemolytic

Treatment of chronic hepatitis C virus (HCV) is limited by substantial side effects including ribavirin-induced hemolytic anemia. Taribavirin, a ribavirin prodrug, was designed to concentrate within the liver to target HCV-infected hepatocytes while minimizing distribution within red blood cells (RBCs) and the subsequent development of hemolytic anemia.. The objective of the review is to evaluate the efficacy and safety of taribavirin as compared with ribavirin in the treatment of chronic HCV infections. A PubMed search was performed using the following key words: viramidine, taribavirin and ribavirin analog. Additional sources included press releases on preliminary results of clinical trials of taribavirin and abstracts presented at international meetings. The literature suggests that weight-based dosing of taribavirin at 25 mg/kg demonstrates lower rates of hemolytic anemia with comparable rates of sustained virologic response (SVR) and is the optimum dose for further studies comparing the efficacy of taribavirin with weight-based dosing of ribavirin.. Failure to eradicate HCV may be associated with extrahepatic viral replication. The dosing strategy of taribavirin favors concentration within the liver to reduce treatment-limiting rates of anemia but may be insufficient to prevent virologic relapse.

Topics: Anemia, Hemolytic; Antiviral Agents; Female; Hepacivirus; Hepatitis C; Humans; Male; Prodrugs; Ribavirin

Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.. All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C. American Association for the Study of Liver Diseases.

Topics: Adolescent; Adult; Anemia, Hemolytic; Antiviral Agents; Body Weight; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome; Viral Load

Today, treatment of chronic hepatitis C is based on a synergistic combination of pegylated interferon and ribavirin with antiprotease inhibitors. Haemolytic anaemia, which is the major side effect of ribavirin treatment, disrupts ribavirin treatment compliance and varies significantly from one patient to another. There is an individual susceptibility to ribavirin haemolysis. With a view to studying haemolysis, and thus optimizing the treatment response, we have developed a new in vitro tool for analysing the ribavirin-induced lysis of red blood cells.. Resuspended red blood cells were incubated with isotonic buffer and a range of concentrations of ribavirin. Haemolysis was quantified by spectrophotometric measurement of the supernatant at 540 nm. The assay was used to test the effects of various compounds and to investigate the susceptibility of patients to haemolytic anaemia.. In our assay, the degree of haemolysis is dependent on the ribavirin concentration used and can be inhibited by the addition of dipyridamole (50% inhibitory concentration [IC(50)] 30 μM), ATP or glutathione (IC(50) 1.63 mM and 767 μM, respectively). We observed a strong decrease in red blood cell haemolysis in the presence of the ribavirin prodrug viramidine (Taribavirin(®)). When testing the performance of this assay with blood from 24 patients before treatment, we observed a strong correlation between in vitro haemolysis before treatment and the decrease in haemoglobin levels seen in vivo during subsequent treatment (P<0.001).. With this new tool it is possible to better evaluate individual susceptibility to ribavirin-induced haemolysis before the start of treatment. In addition, this model will enable the mechanism of ribavirin-induced anaemia to be further explored and allow molecules that could reduce ribavirin haemolysis to be screened and tested in vitro. This approach could help optimize current and future therapeutic strategies involving ribavirin in the treatment of chronic hepatitis C.

Topics: Adenosine Triphosphate; Adult; Anemia, Hemolytic; Dipyridamole; Drug Evaluation, Preclinical; Drug Therapy, Combination; Erythrocytes; Glutathione; Hematologic Tests; Hemolysis; Hepacivirus; Hepatitis C, Chronic; Humans; Inhibitory Concentration 50; Interferon alpha-2; Interferon-alpha; Poliovirus; Polyethylene Glycols; Prodrugs; Recombinant Proteins; Ribavirin; RNA, Viral

Topics: Anemia, Hemolytic; Antiviral Agents; Hepatitis C, Chronic; Humans; Ribavirin

Ribavirin is ineffective against hepatitis C virus as mono-therapy but is critical in attaining both early virologic response and sustained virologic response when combined with pegylated interferon. Ribavirin has significant dose-limiting toxicities, the most important of which is hemolytic anemia. Taribavirin is a ribavirin pro-drug, which targets the liver and has less incidence of anemia, and it may be a promising alternative to ribavirin in the future.

Topics: Anemia, Hemolytic; Antiviral Agents; Carbamates; Hepacivirus; Hepatitis C; Humans; IMP Dehydrogenase; Mycophenolic Acid; Phenylurea Compounds; Ribavirin