Development of Drug Resistance in Patients Treated with HCV Protease Inhibitor
Telaprevir (VX-950) Telaprevir
(VX-950) is a hepatitis C virus (HCV) NS34A protease inhibitor currently undergoing
clinical development. In studies to date, it has shown strong antiviral activity.
But
HCV replicates rapidly with many errors, allowing for the rapid development of
resistance to most directly targeted antiviral agents.
As
reported in the May 2007 issue of Gastroenterology, German researchers
used a highly sensitive sequencing method to analyze mutations in the HCV NS3
protease catalytic domain of approximately 80 clones/sample from patients with
genotype 1 virus who received telaprevir at 1 of 3 dose levels for 14 days:
•
450 mg every 8 hours;
•
750 mg every 8 hours;
•
1250 mg every 12 hours.
Results
•
Mutations that confer
low-level resistance (V36A/M, T54A, R155K/T, and A156S) and high-level resistance
(A156V/T, 36+155, 36+156) to telaprevir were detected and correlated with telaprevir
exposure and virological response.
•
Changes in the frequency
of mutations after the end of dosing showed an inverse relationship between in
vivo viral fitness and resistance.
•
In the absence of
telaprevir selective pressure, the majority of resistant HCV variants were replaced
by wild-type virus within 3-7 months.
Conclusions
"Resistant
HCV isolates are selected rapidly during therapy with the highly active protease
inhibitor telaprevir," the authors concluded. "Combination therapy with
pegylated interferon-alfa or other direct antiviral drugs seem mandatory to avoid
developing resistance."
Many
experts believe that in the future, treatment for HCV will come to resemble that
for HIV, using combinations of drugs -- ideally including agents from different
classes -- in an effort to slow the emergence of resistance.
06/22/07
Reference C
Sarrazin, TL Kieffer, D Bartels, and others. Dynamic hepatitis C virus genotypic
and phenotypic changes in patients treated with the protease inhibitor telaprevir.
Gastroenterology 132(5): 1767-1777. May 2007.
