Baseline hepatitis C virus (HCV) NS3 polymorphisms and their impact on treatment response in clinical studies of the HCV NS3 protease inhibitor faldaprevir.
A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P = 0.47) or treatment naive (62% compared to 66%; P = 0.72).
Boehringer Ingelheim Canada Ltd., R&D, Laval, Quebec, Canada.
Kristi L
KL
Berger
Ibtissem
I
Triki
Mireille
M
Cartier
Martin
M
Marquis
Marie-Josée
MJ
Massariol
Wulf O
WO
Böcher
Yakov
Y
Datsenko
Gerhard
G
Steinmann
Joseph
J
Scherer
Jerry O
JO
Stern
George
G
Kukolj
D019943:Amino Acid Substitution; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016903:Drug Monitoring; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D009154:Mutation; D009842:Oligopeptides / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011804:Quinolines; D013844:Thiazoles / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D007930:Leucine; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552340:faldaprevir