Methods: NS3/4A, NS5A and NS5B regions from the first 69 of 150 genotype 1a and 1b (GT1a/b) viruses from PWID in a trial examining 3 models of care for HCV treatment between 11/2013 and 11/2015 were sequenced based on anticipated DAA regimen. Antiviral agents included interferon (IFN), ribavirin (RBV), simeprevir (SMV), sofosbuvir (SOF), and ledipasvir (LDV). Variants relative to genotype/subtype specific H77 (GT1a) and Con1 (GT1b) reference sequences were reported.
Results: We studied 69 HCV GT1a (N=65) and GT1b (N=5) infected PWID. Regimens included SMV/SOF N=12, SOF/RBV ± IFN N=33, and SOF/LDV N=24. Of the 65 (94.2%) TN PWID, 18/65 (27.7%) had RAVs at BL – 9/12 (75%) NS3, 7/24 (29.2%) NS5A, 2/65 (3.1%) NS5B. RAVs included: NS3 V36M/L N=2, T54S N=1, V55A/I N=3, Q80K/L N=5, I132V N=1; NS5A M28V N=4, L31M N=1, H54Y N=1, H58P N=1; NS5B S556G/R N=2. Of the 4 TE patients, 1 had a BL Q80K. Six (8.7%) patients failed therapy – 1 SMV/SOF, 3 SOF/RBV, 2 SOF/LDV. Only the SMV/SOF failure had a BL RAV (Q80K). This patient became HCV RNA positive at 24 weeks at which time a different set of viral variants were observed and the Q80K was no longer present. RAVs were not detected following SOF/RBV failure. Both SOF/LDV failures had NS5A mutations (Q30H/R, Y93H) post-BL.
Conclusion: RAVs were present among a subset of TN PWID, particularly in NS3. Some RAVs appeared enriched compared to expected prevalence in DAA-naïve individuals. The BL RAVs observed did not affect treatment outcomes. One possible reinfection event was observed based on pre/post-BL variants. Re-treatment options may be limited among patients who fail SOF/LDV given selection of NS5A RAVs. The potential for transmitted NS5A RAVs could pose a particular concern for treatment of PWID.
Y. Lie, Monogram Biosciences: Employee , Salary
L. Agyemang, None
A. Litwin, Gilead Sciences: Scientific Advisor , Consulting fee and Research grant
Merck Pharmaceuticals: Scientific Advisor , Consulting fee and Research grant
Bristol-Myers Squibb: Scientific Advisor , Consulting fee
Janssen Pharmaceutica: Scientific Advisor , Consulting fee
Abbvie: Scientific Advisor , Consulting fee