Research
shows that adding ribavirin to pegylated interferon reduces the likelihood of
HCV relapse during or after therapy, but use of ribavirin is limited by the development
of anemia. Taribavirin
(also known as Viramidine), a prodrug of ribavirin that targets the liver,
is associated with less toxicity to red blood cells.
As reported recently,
the Phase III VISER
1 and VISER
2 studies showed that while taribavirin was significantly less likely than
ribavirin to cause anemia (5%-6% vs 22%-24%), it also was less effective, producing
sustained virological response (SVR) rates of 38%-40% vs 52%-55% when combined
with pegylated interferon. However, there was a trend toward greater efficacy
among patients with higher exposure to taribavirin on the basis of body weight.
Two
studies presented at the recent American Association for the Study of Liver Diseases
(AASLD) annual meeting provided further information on outcomes with higher taribavirin
exposure levels. Study 1
Previous
studies have shown that the later a patient experiences HCV RNA suppression during
the course of treatment with pegylated interferon plus ribavirin, the more likely
they are to relapse and the lower the likelihood of ultimately achieving SVR.
To
understand why taribavirin was associated with a lower SVR in VISER 1, researchers
conducted a post-hoc analysis of the intent-to-treat population to examine the
impact of treatment on viral kinetics and its association with factors such as
patient age, body weight, and total taribavirin drug exposure.
In VISER
1, 970 patients were randomly assigned (in a 2:1 ratio) to receive either fixed-dose
taribavirin or weight-base ribavirin, in combination with pegylated interferon
alpha-2b (PegIntron). Subjects were stratified on the basis of HCV genotype, baseline
HCV viral load, and body weight. Results
Patients who
achieved rapid virological response (RVR) at Week 4 had an SVR rate approaching
90% when treated with either taribavirin or ribavirin.
Patients who had slower virological response -- in particular those who failed
to achieve at least a 2-log drop in HCV RNA within the first 4 weeks of therapy
-- had a marked increase in SVR when treated with taribavirin compared with ribavirin
(63% vs 36%) if HCV RNA was undetectable at Week 12.
If HCV RNA was undetectable at Week 24, the respective SVR rates were 23% and
12%.
In
conclusion, the researchers suggested, "The improvement in SVR in patients
who fail to clear HCV RNA early during treatment is likely secondary to the improved
tolerability of taribavirin over ribavirin."
Taribavirin
Ribavirin
Week 4 / Week 12 / Week 24 HCV RNA response
N
age
< 45 years, %
mean
dose
mg/kg
SVR
%
N
age
< 45 years, %
mean
dose
mg/kg
SVR
%
neg / neg
/ neg
144
71%
16.4
87%
103
58%
14.8
88%
≥
2 log drop / neg / neg
146
49%
16.1
57%
73
32%
14.7
78%
<
2 log drop / neg / neg
24
50%
15.6
63%
14
36%
13.7
36%
≥
2 log drop / ≥ 2 log drop / neg
27
30%
15.6
26%
10
40%
12.6
20%
< 2 log drop / ≥ 2 log drop / neg
35
37%
15.8
23%
25
56%
14.7
12%
neg
= undetectable HCV RNA
Study 2
The
second analysis, also from VISER 1, looked at the impact of taribavirin and ribavirin
exposure based on weight with regards to both virological efficacy and rates of
anemia, defined as a hemoglobin level less than 10 g/dL.
Results
Higher mg/kg taribavirin exposure resulted in increased efficacy, while anemia
rates remained relatively constant.
Despite having the same drug exposure, patients with HCV genotype 2 or 3 treated
for 24 weeks experienced less anemia compared to patients with other genotypes
treated for 48 weeks.
The risk of hemoglobin decline was present throughout the course of therapy, not
just during the initial weeks of treatment.
Dosing taribavirin at levels higher than 18 mg/kg yielded response rates similar
to those observed with the current standard of care (pegylated interferon plus
ribavirin). The researchers concluded that, "Future studies should be
directed at examining higher drug exposures (mg/kg) of taribavirin to maximize
efficacy potential without compromising safety."
Taribavirin dose
N
SVR%
Anemia Rate (%)
All genotypes
≤13
mg/kg
179
32
4
>13-15
mg/kg
147
31
4
> 15-18
mg/kg
182
38
7
> 18 mg/kg
138
52
7
Genotype
2/3
≤13
mg/kg
51
53
4
>13-15
mg/kg
38
63
3
> 15-18
mg/kg
42
64
0
> 18 mg/kg
43
70
2
Genotype
non-2/3
≤13
mg/kg
128
23
4
>13-15
mg/kg
109
20
5
> 15-18
mg/kg
140
30
9
> 18 mg/kg
95
44
8
Hunter Holmes
McGuire VAMC, Richmond, VA; Fundacion de Investigacion de Diego, Piso Oficina,
Puerto Rico; Henry Ford Health System, Detroit, MI; Digestive Disease Center,
Plainview, NY; Scripps Clinic, La Jolla, CA; Hopital Hotel-Dieu, Lyon, France;
Valeant Pharmaceuticals International, Costa Mesa, CA. Weill Medical College,
New York, NY; Scripps Clinic, La Jolla, CA; Hopital La Pitié-Salpétrière
Service d'Hepato-Gastroentérologie, Paris, France; Hospital Vall d'Hebrón,
Barcelona, Spain; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Klinica
Obserwacyjno-Zakazna Akademii Medyczna W Bialymstoku, Bialystok, Poland; Beth
Israel Deaconess Medical Center Harvard Medical School, Boston, MA; Valeant Pharmaceuticals
International, Costa Mesa, CA.
11/17/06
References
M
L Shiffman, M Rodriguez-Torres, S Gordon, and others. Rapid Virologic Response
(RVR) is Enhanced by Higher Drug Exposure Among Patients Receiving Taribavirin
in Combination With Pegylated Interferon alfa-2b for the Treatment of HCV Infection.
57th AASLD. Boston, MA. October 27-31, 2006. Abstract 1146.
I Jacobson,
P Pockros, Y Benhamou, and others. Impact of Taribavirin and Ribavirin Exposure
on Efficacy and Anemia Rates When Combined with Pegylated Interferon Alfa-2b in
the Treatment of Chronic Hepatitis C. 57th AASLD. Boston, MA. October 27-31, 2006.
Abstract 1133.
Research
shows that adding ribavirin to pegylated interferon reduces the likelihood of
HCV relapse during or after therapy, but use of ribavirin is limited by the development
of anemia. 
Patients who
achieved rapid virological response (RVR) at Week 4 had an SVR rate approaching
90% when treated with either taribavirin or ribavirin.
