Telaprevir plus Pegylated Interferon Suppresses Wild-type and Resistant HCV Over
14 Days By
Liz Highleyman
At the recent 57th Annual Meeting of the
American Association for the Study of Liver Diseases in Boston, researchers presented
further data on telaprevir (VX-950), an oral HCV protease inhibitor being developed
by Vertex Pharmaceuticals.
As reported in the October 2006 issue of Gastroenterology,
prior studies showed that telaprevir potently suppressed HCV RNA in genotype 1
patients over 14 days when used alone (4.4 log decline in optimal dose group)
or in combination with pegylated interferon (5.5 log decline).
The present
study looked at telaprevir activity against different HCV strains. In a previous
study, mutations were identified that confer low-level (V36M/A, T54A, R155K/T)
or high-level (A156V/T and 36/155) resistance to telaprevir in vitro. Using a
highly sensitive sequencing assay to detect minor populations of viral variants
(> 5%), researchers performed a kinetic analysis of these variants in
a 14-day study of telaprevir as monotherapy (750 mg every 8 hours; n=8) or used
in combination with pegylated interferon (n=8).
They
isolated plasma HCV RNA at Days 4, 8, 12, and 14 during dosing and 7-10 days after
dosing. The NS3 protease domain cDNA was amplified by nested RT-PCR, cloned, and
sequenced with a lower limit of detection of 100 IU/mL. Sequence changes were
analyzed from about 75 clones/patient/time point.
Results
In patients who received telaprevir plus pegylated interferon, wild-type virus
was detected at Day 4.
Either wild-type or resistant HCV was observed at Day 8 in half of patients (4
out of 8) with HCV RNA levels above the lower limit of detection.
These 8 patients began standard therapy with pegylated interferon plus ribavirin,
and their HCV was undetectable 3 months after the 14-day study period.
Among patients who received telaprevir monotherapy, 4 experienced virological
breakthrough or plateau response.
In these patients, viral variants with the R155 and A156V/T mutations were detectable
by Day 8.
A variant with V36(M/A)/R155(K/T) mutations predominated by Day 14.
4 other patients in the telaprevir monotherapy arm had continuous decline in HCV
RNA.
2 of these patients had variants with A156V/T detected by Day 8, while the other
2 had HCV levels below the lower limit of detection.
Conclusion
"The
rapid and dramatic antiviral response to telaprevir reflects a sharp reduction
in wild-type virus," the researchers wrote in conclusion. "Viral variants
were uncovered as wild-type virus was cleared."
"HCV RNA levels
can decline in patients receiving telaprevir monotherapy, even in those with detectable
A156V/T variant," they added. "Viral rebound with monotherapy appears
to result from the presence of V36(M/A)/R155(K/T); this could be due to greater
fitness of this variant compared to A156V/T."
Finally, they noted
that, "The combination of telaprevir and pegylated interferon suppressed
resistant variants, indicating that these variants are fully sensitive to pegylated
interferon."
Infectious Diseases, Vertex Pharmaceuticals Inc.,
Cambridge, MA; Internal Medicine, Universitätsklinikum des Saarlandes, Homburg,
Germany; Gasteroenterology and Heptology, Academic Medical Center, Amsterdam,
Netherlands.
11/03/06
References
T
Kieffer, C Sarrazin, J Miller, and others. Combination of Telaprevir (VX-950)
and Peg-IFN-alfa Suppresses Both Wild-type Virus and Resistance Variants in HCV
Genotype 1-Infected Patients in a 14-day Phase 1b study. 57th AASLD. October 27-31,
2006. Boston, MA. Abstract 92.
H
W Reesink, S Zeuzem, C J Weegink, and others. Rapid Decline of Viral RNA in Hepatitis
C Patients Treated With VX-950: A Phase Ib, Placebo-Controlled, Randomized Study.
Gastroenterology 131(4): 997-1002. October 2006.
In patients who received telaprevir plus pegylated interferon, wild-type virus
was detected at Day 4.
