Hepatitis C Resistance-Associated Substitutions Among People Who Inject Drugs Treated With Direct-Acting Antiviral-Containing Regimens in the Prevail Study

Author: Matthew A, Reeves J, Feliciano I, Lie Y, Agyemang L, Litwin A

Theme: Clinical Research Year: 2017

Background: Resistance-associated substitutions (RASs) to HCV direct-acting antivirals (DAAs) have been associated with virologic failure and may limit retreatment options. PWID are at highest risk for transmission of resistant virus. We report on RASs at baseline (BL)/following virologic failure in treatment-naïve (TN) and -experienced (TE) methadone-maintained PWID.
Methods: NS3/4A, NS5A and NS5B regions were sequenced from 150 genotype 1 (GT1) viruses from PWID between 11/2013-5/2016. Antiviral agents included interferon (IFN), ribavirin (RBV), telaprevir (TVR), simeprevir (SMV), sofosbuvir (SOF), and ledipasvir (LDV). Reported substitutions were relative to H77 (GT1a) and Con1 (GT1b) reference sequences.
Results: Of 150 PWID, 128 (85.3%) were GT1a and 22 (14.7%) were GT1b. Regimens included TVR/RBV/IFN N=3, SMV/SOF N=11, SOF/RBV±IFN N=32, SOF/LDV N=104. Of 139 (92.7%) TN PWID, 82/139 (59%) had BL RASs – 66/139 (47.5%) in NS3 (V36M/L N=3, T54S N=3, V55A/I N=6, Q80K/L N=55, S122G/N/T N=14, I132V N=1); 24/139 (17.3%) in NS5A (K24K/R N=4, M28V N=10, L31M N=1, H54Y N=1, H58H/P N=7, Y93H/S N=5); 8/139 (5.8%) in NS5B (G307G/R N=2, S473S/T N=1, S556G/R N=5). Of the 11 TE patients, 10 had BL NS3 RASs (V36L N=1, Q80K N=7, S122G N=1, I132V N=1), 4 had BL NS5A RASs (M28V N=3, H58P N=1). Eight (5.3%) patients had virologic rebound – 1 SMV/SOF, 4 SOF/RBV, 3 SOF/LDV. The SMV/SOF rebound had different viral substitutions and lost a BL Q80K at 24 weeks suggestive of reinfection versus outgrowth of a minor variant. One SOF/LDV failure had a baseline H58P; otherwise no class-specific pre-treatment RASs were present. All SOF/LDV failures had NS5A mutations (Q30H/R N=2, H58P, Y93H) post-BL. No RASs were detected following SOF/RBV failure.
Conclusion: Our data show that RAS prevalence among TN PWID is largely comparable to that expected in DAA-naïve individuals. In this cohort, only 2/150 (1.3%) developed new RASs. Therefore, concern for transmission of resistant virus may be minimal based on this cohort of PWID.

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