Using
a highly sensitive sequencing assay that detects minor populations of viral variants
(occurring at ≥ 5%), researchers from Vertex
Pharmaceuticals -- the company
developing telaprevir -- identified HCV mutations that conferred low-level
(V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to the
drug in vitro.
In
the August 6, 2007 advance online edition of Hepatology,
the investigators presented a detailed kinetic analysis of these variants in 16
patients treated with telaprevirmonotherapy
or telaprevir plus pegylated
interferon alpha-2a (Pegasys) for 14 days.
Results
•In
4 patients who experienced viral rebound while taking 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 who received telaprevir alone
or with pegylated interferon, the A156V/T variant was
detected in some patients, but viral levels continued to decline in all patients.
Conclusion
“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,” the authors concluded.
“In
patients given telaprevir alone, viral rebound can result
from the selection of variants with greater fitness,” they added. “However, the
combination of telaprevir
and pegylated interferon alpha-2a inhibited both wild-type
and resistant variants.”
In
the present study, they noted, “every patient who began pegylated
interferon alpha-2a and ribavirin after the 14-day [telaprevir] dosing period had undetectable HCV RNA levels
at 24 weeks, indicating that telaprevir-resistant variants
are sensitive to pegylated interferon alpha-2a and ribavirin.”
08/17/07
Reference TL Kieffer, C Sarrazin, JS Miller,
and others.Telaprevir and pegylated interferon-alpha-2a
inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.
Hepatology. August 6, 2007 [Epub ahead of print].
