Baseline prevalence and emergence of protease inhibitor resistance mutations following treatment in chronic HCV genotype-1-infected individuals.
BACKGROUND
The HCV NS3/4A serine protease inhibitors (PIs) boceprevir (BOC), telaprevir (TVR) and simeprevir (SMV) are approved for treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin. The present study investigated the prevalence of HCV NS3 drug resistance mutations (DRMs) associated with HCV genotype-1-infected individuals at baseline and in viral breakthrough following BOC and TVR treatment.


METHODS
HCV genotype-1-infected individuals were enrolled in a multicentre, prospective outcomes study. The HCV NS3 viral protease was analysed for DRMs at baseline (n=164) and at viral breakthrough (n=18) following BOC/TVR treatment.


RESULTS
Viral NS3 protease subtype analysis showed 65.2% (107/164) were HCV subtype-1a and 34.8% (57/164) were HCV subtype-1b infections. Naturally occurring PI DRMs in NS3 (V36L, T54S, V55A, Q80K/R and I132V) were identified in 57.3% (94/164) cases at baseline. The NS3 Q80K polymorphism was found in 43/107 (40.2%) of HCV subtype-1a and exclusively in clade 1 (43/82; 52.4%) versus clade 2 viruses (0/25; 0%, P<10(-6)). The pretreatment I132V variant was found in 78.9% (45/57) of subtype-1b. Of 18 patients who had viral breakthrough, the majority was subtype-1a (77.8%, 14/18). BOC/TVR-associated DRMs were detected in 94.4% (17/18), of which 64.7% (11/17) emerged on-treatment.


CONCLUSIONS
To ensure the most appropriate direct-acting antiviral-based treatment regimen is employed, baseline reporting of clade and resistance mutations for HCV subtype-1a using nucleotide sequence-based analysis is warranted prior to commencement of therapy.
Ireland Vietnam Blood-Borne Virus Initiative (IVVI), Dublin, Ireland and Hanoi, Vietnam. crid.office@ucd.ie.
Linh Thuy
LT
Nguyen
Emma
E
Gray
Jonathan
J
Dean
Michael
M
Carr
Jeff
J
Connell
Cillian
C
De Gascun
Lan Anh
LA
Nguyen
Aisling
A
O'Leary
Colm
C
Bergin
William
W
Hall
Suzanne
S
Norris
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000453:epidemiology* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011480:Protease Inhibitors / Q000627:therapeutic use; D019233:Retreatment; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases