taribavirin and Hepatitis-C

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

Several advances afford promise for improving the management of hepatitis C virus (HCV) infection. Current therapies primarily target the immune system; the now proven ability to culture the entire virus in vitro could ultimately facilitate the identification of therapies directly targeting viral replication. Several therapies are presently in development. Taribavirin hydrochloride (Viramidine, Valeant Pharmaceutical International, Singapore), a ribavirin prodrug, has shown promise, although the rate of sustained virologic response with this agent has been disappointing. The next generation of antivirals will consist of protease and polymerase inhibitors, a number of which are undergoing investigation, initially as monotherapy and subsequently in combination with pegylated interferon and ribavirin. Challenges include the prevention of recurrent HCV infection in liver-transplant recipients and development of a safe and effective HCV vaccine.

Topics: Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Nucleic Acid Synthesis Inhibitors; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin; Viral Vaccines; Virus Replication

Topics: Adenine; Antiviral Agents; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Lamivudine; Mutation; Oligopeptides; Organophosphonates; Proline; Ribavirin; Serine Proteinase Inhibitors

Chronic infection with hepatitis C virus (HCV) can progress to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The current best treatment for HCV infection is combination therapy with pegylated interferon and ribavirin. Although this regimen produces sustained virologic responses (SVRs) in approximately 50% of patients, it can be associated with a potentially dose-limiting hemolytic anemia. Hemoglobin concentrations decrease mainly as a result of ribavirin-induced hemolysis, and this anemia can be problematic in patients with HCV infection, especially those who have comorbid renal or cardiovascular disorders. In general, anemia can increase the risk of morbidity and mortality, and may have negative effects on cerebral function and quality of life. Although ribavirin-associated anemia can be reversed by dose reduction or discontinuation, this approach compromises outcomes by significantly decreasing SVR rates. Recombinant human erythropoietin has been used to manage ribavirin-associated anemia but has other potential disadvantages. Viramidine, a liver-targeting prodrug of ribavirin, has the potential to maintain the virologic efficacy of ribavirin while decreasing the risk of hemolytic anemia in patients with chronic hepatitis C.

Topics: Anemia; Antiviral Agents; Cardiovascular System; Cognition Disorders; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemoglobins; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Ribavirin

New strategies have led to better results in the treatment of HCV infection during the last few years. At present the recommended treatment for patients with chronic hepatitis C is a combination of pegylated interferon and ribavirin. The sustained virological response rate of this combination therapy is 42 - 48 % for patients with genotype 1 after a course of 48 weeks and 80 % for patients with genotype 2 or 3 after a course of 24 weeks. New nucleoside analogs may lead to a better tolerance and better outcomes. A new approach is the long term monotherapy with pegylated interferon in order to reduce the progression of fibrosis and the incidence of cirrhotic complications. At present the effectivity of protease inhibitors and of a therapeutic immunisation with the E1 envelope protein of the hepatitis C virus are being examined. Because the optimal treatment strategy for patients with an acute hepatitis C infection is still unclear, these patients should be included in clinical studies.

Topics: Acute Disease; Amantadine; Animals; Antiviral Agents; Hepacivirus; Hepatitis B; Hepatitis C; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Recurrence; Ribavirin; Transaminases; Treatment Failure; Viral Envelope Proteins; Viral Hepatitis Vaccines

Viramidine, an analog of ribavirin is a broad-spectrum antiviral under development by Ribapharm (previously the R&D division of ICN Pharmaceuticals) for the potential treatment of viral infections [378507]. In September 2000, phase I trials began in Europe. In December 2001, the company filed a US IND for the clinical development of viramidine as part of a combination therapy with interferon-afor the treatment of chronic hepatitis C virus (HCV) infection [435007], [441613]; a phase I trial was initiated in the US in late March 2002 [435598]. In November 2002, Ribapharm reported that it would start phase II trials of viramidine in the treatment of chronic HCV by the end of 2002 [469062].

Topics: Animals; Clinical Trials as Topic; Hepatitis C; Humans; Ribavirin; Technology, Pharmaceutical

Ribavirin, in combination with interferons, has proved clinically useful for the treatment of hepatitis C virus (HCV) infection despite uncertainty as to its true mechanism of action. Its immunomodulatory effects have been proposed to be crucial for its efficacy in HCV treatment. Two new derivatives of zibavirin, Levovirin and virmidine, are currently in development as HCV therapeutics. Both drugs retain ribavirin's immunomodulatory properties but appear to be less toxic than the parent drug. Clinical evaluation of these drugs may aid in understanding the relevant mechanism of action of ribavirin itself, as well as the role of immunomodulators in HCV therapy.

Topics: Antiviral Agents; Hepatitis C; Humans; Ribavirin; Stereoisomerism

The current study was carried out to evaluate pharmacokinetic profiles of viramidine and ribavirin in patients (n = 8 per dose group) with compensated hepatitis C infection following oral dosing of viramidine (400, 600, or 800 mg bid for 4 weeks). Pharmacokinetic parameters were determined on days 1 and 29 based on plasma, red blood cell, and urine concentrations of viramidine and ribavirin. The results indicate rapid absorption and conversion of viramidine to ribavirin after oral administration of viramidine. Viramidine and ribavirin exposure in plasma and RBCs generally increased from the 400- to 600-mg dose level of viramidine. However, no further increase in exposure was noted at the 800-mg dose. Long half-lives for viramidine (66-76 hours in plasma and 200-420 hours in red blood cells) and ribavirin (340-410 hours in plasma and 360-430 hours in red blood cells) were noted. A negligible amount of viramidine (1%-4% of dose) and a small amount of ribavirin (9%-14% of dose) were excreted in the urine. The renal clearance was low for both viramidine (5-8 L/h) and ribavirin (4-7 L/h). Significant accumulation of viramidine was noted in red blood cells (accumulation factor [R] = 5-8) but not in plasma (R = 2). Extensive accumulation of ribavirin was noted in both plasma (R = 9-17) and red blood cells (R = 77-129). Steady-state levels of ribavirin and viramidine in plasma and red blood cells were achieved by day 22. At steady state, there was extensive conversion of viramidine to ribavirin in both plasma and red blood cells. Both viramidine and ribavirin were preferentially distributed into red blood cells than plasma.

Topics: Administration, Oral; Adult; Antiviral Agents; Erythrocytes; Female; Hepatitis C; Humans; Male; Middle Aged; Prodrugs; Ribavirin

Topics: Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Drug Delivery Systems; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Neoplasms; Ribavirin; Treatment Outcome

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

Topics: Antiviral Agents; Biomedical Research; Drug Design; Hepatitis C; Humans; Oligopeptides; Pyrimidine Nucleosides; Recombinant Fusion Proteins; Ribavirin; Toll-Like Receptors

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Hepatitis C; Humans; Ribavirin; Treatment Outcome