Standard therapy for chronic hepatitis C virus (HCV) infection consists of pegylated interferon alfa-2a (Pegasys) or alfa-2b (PegIntron) plus ribavirin. Adding ribavirin significantly lessens the risk of relapse after treatment, but it can cause a type of red blood cell damage known as hemolytic anemia, requiring some patients to lower their doses or stop taking the drug.

Taribavirin is a pro-drug of ribavirin that does not enter red blood cells as easily and is therefore less likely to cause anemia. In earlier trials, taribavirin used at a fixed dose was not as effective as ribavirin, but it did reduce the likelihood of developing anemia. People who received higher taribavirin doses relative to their body weight, however, had better responses, leading investigators to conduct a trial of higher doses adjusted according to weight.

Below is an edited excerpt from a press release issued by Wiley-Blackwell, publisher of Hepatology, describing the study and its findings.

Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C

Weight-based taribavirin reduces anemia, increases sustained virologic response

Researchers at Cedars-Sinai Medical Center and 50 other centers found that weight-based dosing of taribavirin reduces rates of anemia while increasing sustained virologic response (SVR) in patients with chronic hepatitis C (HCV). Full details of this study are available in the October issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

Chronic HCV is typically treated with ribavirin. When used in combination with peginterferon alfa (peg-IFN), ribavirin significantly enhances on-treatment virologic response and reduces relapse. However, ribavirin, particularly the combination of interferon and ribavirin, is associated with hemolytic anemia, a significant toxicity resulting from the accumulation of ribavirin in red blood cells. Taribavirin, formerly known as viramidine, is a nucleoside analog and oral pro-drug of ribavirin that is less able to enter red blood cells, and should therefore be associated with significantly less anemia.

This theory was demonstrated in two previous phase 3 trials. While statistically less anemia was observed in patients treated with taribavirin compared to ribavirin, the primary efficacy endpoint of these studies, a non-inferior SVR between the taribavirin and ribavirin, was not achieved. Detailed subgroup analyses of the data suggest fixed dosing as opposed to weight-based dosing, and the selection of an inadequate dose, are to blame. The present multi-center study explored several higher weight-based doses of taribavirin to determine a dosage regimen that was able to deliver comparable responses to ribavirin with fewer incidences of anemia.

A phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive, genotype 1 patients stratified by body weight and baseline viral load at 51 centers in the United States between March 2007 and October 2008. Patients were randomized 1:1:1:1 to receive taribavirin (20, 25, or 30 mg/kg/day) or ribavirin (800 -1400 mg/day) with pegylated interferon alfa-2b for 48 weeks.

The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at treatment week 12. Additional efficacy endpoints included SVR, undetectable HCV RNA at treatment weeks 4, 24 and 48, and viral relapse for those who were responders at the end of treatment. A total of 86 (41%) of taribavirin patients and 25 (36%) of the ribavirin group completed treatment and follow up. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%).

The present study demonstrated that weight-based dosing of taribavirin achieved comparable efficacy to ribavirin as demonstrated by SVR. This was observed in all three taribavirin weight-based dose treatment groups, which met the study's primary end-point. Patients treated with taribavirin had less than half the anemia compared to ribavirin treated patients. These results suggest weight-based dosing of taribavirin can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.

Notably, fewer patients treated with taribavirin required dose reductions (13%-28%) compared to 32% of patients treated with ribavirin. Less frequent dose modification in patients treated with taribavirin may alleviate the need to utilize erythropoiesis-stimulating agents (ESAs)[e.g., erythropoietin, brand names Epogen or Procrit]. Several studies have demonstrated the use of ESAs can significantly decrease the need to dose reduce ribavirin and leads to an improvement in the quality of life during HCV treatment, but fails to improve the SVR. The use of ESAs also adds significant cost to HCV treatment and is associated with serious adverse events including thrombosis and red cell aplasia.

Lead investigator Dr. Fred Poordad concludes, "These data suggest taribavirin may be an effective agent to substitute for ribavirin in the future and could be incorporated in upcoming trials utilizing emerging small molecules for HCV treatment [i.e., HCV protease and polymerase inhibitors]."

Editorial author Dr. Paul Kwo comments, "If taribavirin can be shown to preserve or improve efficacy rates in combination with direct-acting antiviral agents (DAAs) and peg-IFN, with lower rates of anemia, the use of taribavirin in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat. Taribavirin may have a role in populations particularly sensitive to ribavirin-related anemia. However, with the commencement of several trials comprising of multiple combinations of DAAs with and without peg-IFN/ribavirin, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of taribavirin remains less precisely defined and could potentially have a finite life cycle."

Investigator affiliations: Cedars-Sinai Medical Center, Los Angeles, CA; ?Alamo Medical Research, San Antonio, TX; ?McGuire Research Institute, McGuire Veterans Administration Medical Center, Richmond, VA; Southern California Liver Centers, San Clemente, CA; Duke Clinical Research Institute, Duke University, Durham, NC; Saint Louis University School of Medicine, St. Louis, MO; Valeant Pharmaceuticals North America, Aliso Viejo, CA.

10/1/10

References

F Poordad, E Lawitz, ML Shiffman, and others. Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C. Hepatology 52(4): 1208-1215 (Abstract). October 2010.

P Kwo and R Vinayek. The next step for taribavirin (Editorial). Hepatology. 52(4): 1185-1188. October 2010.

Other Source

Wiley-Blackwell. Taribavirin offers a safe, effective alternative for chronic hepatitis C. Media advisory. September 22, 2010.