Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir.
OBJECTIVE
Telaprevir (VX-950), a hepatitis C virus (HCV) NS3.4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur.


METHODS
A highly sensitive sequencing method was developed in which approximately 80 clones/sample were analyzed to identify mutations in the NS3 protease catalytic domain in HCV genotype-1-infected patients dosed with 450 mg every 8 hours, 750 mg every 8 hours, or 1250 mg every 12 hours of telaprevir for 14 days.


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 virologic 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 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. Combination therapy with pegylated interferon-alfa or other direct antiviral drugs seem mandatory to avoid developing resistance.
Sarrazin
Christoph
C
Klinik für Innere Medizin II, Universität des Saarlandes, Homburg/Saar, Germany.
Kieffer
Tara L
TL
Bartels
Doug
D
Hanzelka
Brian
B
Müh
Ute
U
Welker
Martin
M
Wincheringer
Dennis
D
Zhou
Yi
Y
Chu
Hui-May
HM
Lin
Chao
C
Weegink
Christine
C
Reesink
Henk
H
Zeuzem
Stefan
S
Kwong
Ann D
AD
D020134:Catalytic Domain / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000254:growth & development*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins; D012697:Serine Endopeptidases / Q000235:genetics; D013997:Time Factors; D017361:Viral Nonstructural Proteins; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D004279:DNA, Viral; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C100416:peginterferon alfa-2a