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.
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
Below is an edited excerpt from a press release issued by Wiley-Blackwell,
publisher of Hepatology, describing the study and its
Offers a Safe, Effective Alternative for Chronic Hepatitis C
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.
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).
P Kwo and R Vinayek. The next step for taribavirin (Editorial).
Hepatology. 52(4): 1185-1188. October 2010.
Taribavirin offers a safe, effective alternative for chronic
hepatitis C. Media advisory. September 22, 2010.