Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens.
Daclatasvir (DCV) is a pan-genotypic non-structural protein 5A (NS5A) inhibitor that is approved for treatment of hepatitis C virus (HCV) genotype (GT)1 and GT3 in the USA and GT1, GT3 and GT4 in Europe. We set out to examine the impact of daclatasvir-based regimens on the sustained virologic response (SVR) in patients with GT2 infection with respect to GT2 subtype and NS5A polymorphisms at amino acid positions associated with daclatasvir resistance.



Analyses were performed on 283 GT2 NS5A sequences from five daclatasvir regimen-based clinical trials (ClinicalTrials.gov: NCT-01257204, NCT-01359644, NCT-02032875, NCT-02032888 and NCT-01616524) and 143 NS5A sequences from the Los Alamos HCV database. Susceptibility analyses of substitutions at amino acid positions associated with daclatasvir resistance and patient-derived NS5A sequences were performed using an in vitro HCV replication assay.



Of 13 GT2 subtypes identified from 426 NS5A sequences, the most prevalent were GT2a (32%), GT2b (48%) and GT2c (10%). The most prevalent NS5A polymorphism was L31M (GT2a = 88%; GT2b = 59%; GT2c = 10%). Substitutions identified in 96% of GT2 NS5A sequences exhibited daclatasvir EC50values ranging from 0.005 to 20 nM when tested in vitro. A similar range in daclatasvir EC50values was observed for 16 diverse GT2 patient-derived NS5A sequences (EC50= 0.005-60 nM). Depending on the daclatasvir-based regimen studied (daclatasvir/interferon-based or daclatasvir/sofosbuvir-based), SVR rates ranged from 90% to 100% in GT2 patients with the most prevalent baseline NS5A-L31M polymorphism, compared with from 96% to 100% without this polymorphism.



High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Nannan
N
Zhou
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Zhou
Z
Han
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Sandra
S
Hartman-Neumann
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Brenda
B
DeGray
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Joseph
J
Ueland
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Vincent
V
Vellucci
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA.
Dennis
D
Hernandez
Bristol-Myers Squibb R&D, Wallingford, CT 06492, USA fiona.mcphee@bms.com.
Fiona
F
McPhee
D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates; D002986:Clinical Trials as Topic; D024882:Drug Resistance, Viral; D005060:Europe; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011759:Pyrrolidines; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014481:United States; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir