Two Recent Articles Focus on the Use of Telaprevir (VX-950) plus
Pegylated Interferon Alfa-2a (Pegasys) in Patients with Chronic Hepatitis C
Telaprevir
(VX-950), a promising new experimental HCV protease inhibitor, has been shown
to significantly decrease HCV
RNA in patients with chronic hepatitis C.
Two articles published in the September 2007 issue of Hepatology focus
on the use of telaprevir
in combination with pegylated
interferon alfa-2a (Pegasys). Preliminary data from these studies were presented
in 2006 at the 57th American Association for the Study of Liver Diseases (AASLD)
meeting.
Antiviral
Activity of Telaprevir with or without Pegylated Interferon Alfa-2a
In
the first study, Nicole Forestier and colleagues evaluated viral kinetics and
safety during dosing with telaprevir alone and in combination with pegylated interferon
alfa-2a for 14 days.
Previously
untreated patients with genotype 1 chronic hepatitis C were randomly assigned
to receive placebo plus pegylated interferon alfa-2a (n = 4); telaprevir alone
(n = 8); or telaprevir plus pegylated interferon alfa-2a (n = 8).
Telaprevir
was given as 750 mg oral doses every 8 hours; pegylated interferon alfa-2a was
given as 180 microgram subcutaneous injections once weekly.
Results
•
The median decrease in HCV RNA from baseline to day 15 was 1.09 log10 in the placebo
plus pegylated interferon alfa-2a group, 3.99 log10 in the telaprevir monotherapy
group, and 5.49 log10 in the telaprevir plus pegylated interferon alfa-2a group.
•
HCV RNA levels were
undetectable on day 15 in 4 patients who received telaprevir plus pegylated interferon
alfa-2a and in 1 patient who received telaprevir alone.
•
No viral breakthrough
occurred in patients who received telaprevir plus pegylated interferon alfa-2a.
•
The majority of adverse
events were mild.
•
There were no serious
adverse events or premature treatment discontinuations.
•
12 weeks after starting
standard therapy (pegylated interferon plus ribavirin) at the end of the study
dosing period, HCV RNA was undetectable in all 8 patients in the telaprevir plus
pegylated interferon alfa-2a group, 5 patients in the telaprevir monotherapy group,
and 1 patient in the placebo plus pegylated interferon alfa-2a group.
In
conclusion, the study authors wrote, "This study confirmed the substantial
antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir
combined with peginterferon alfa-2a."
Telaprevir
plus Peginterferon Alfa-2a Inhibits Both Wild-type and Resistant HCV Variants
In
the second study, Tara L. Kieffer and colleagues used a highly sensitive sequencing
assay that detects minor populations of viral variants (5%) to identify mutations
that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and
36/155) resistance to telaprevir in vitro.
The
investigators reported a detailed kinetic analysis of these variants in 16 patients
given telaprevir alone or telaprevir plus pegylated interferon alfa-2a for 14
days.
Results
•
In 4 patients who
experienced viral rebound while on telaprevir alone, the R155K/T and A156V/T variants
were detected during the initial steep decline in HCV RNA.
•
During the rebound
phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double
mutant variants.
•
In the remaining 12
patients given telaprevir alone or with telaprevir plus pegylated interferon alfa-2a,
the A156V/T variant was detected in some patients, but viral levels continued
to decline in all patients.
Based
on these results, the study authors concluded, "These studies suggest that
the initial antiviral response to telaprevir is due to a sharp reduction in wild-type
virus, which uncovers pre-existing telaprevir-resistant variants. In patients
given telaprevir alone, viral rebound can result from the selection of variants
with greater fitness."
"However,
the combination of telaprevir and peginterferon alfa-2a inhibited both wild-type
and resistant variants," they continued.
Finally,
they stated, "In the present study, every patient who began peginterferon
alfa-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA
levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive
to peginterferon alfa-2a and ribavirin."
09/07/07
References
N
Forestier, H W Reesink, J Christine , and others. Antiviral activity of telaprevir
(VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology
46(3): 640-648. September 2007.
T
L Kieffer, C Sarrazin, J S Miller, and others. Telaprevir and pegylated interferon-alpha-2a
inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
Hepatology 46(3): 631-639. September 2007.
Hepatology is
published by John Wiley & Sons on behalf of the American Association for the
Study of Liver Diseases (AASLD).
