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Hepatitis C Resistance-Associated Variants Among People Who Inject Drugs Treated With Direct-Acting Antiviral-Containing Regimens

Year: 2016

Type: article

Abstract: Background. Resistance-associated variants (RAVs) to HCV direct-acting antivirals (DAAs) have been associated with virologic failure and may limit retreatment options. People who inject drugs (PWID) are the main driver of the HCV epidemic and are at highest risk for HCV transmission and reinfection. In this study, we report on RAVs at baseline (BL) and following virologic failure in treatment-naive (TN) and -experienced (TE) methadone-maintained PWID. 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 November 2013 and November 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 of 65 (27.7%) had RAVs at BL: 9 of 12 (75%) NS3, 7 of 24 (29.2%) NS5A, 2 of 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-naive 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. Disclosures. M. Akiyama, Gilead Sciences: Grant Investigator, Grant recipient; J. Reeves, Monogram Biosciences: Employee and Shareholder, Salary; Y. Lie, Monogram Biosciences: Employee, Salary; 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

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofw172.318

Authors: Matthew Akiyama, Jacqueline Reeves, Yolanda Lie, Linda Agyemang, Alain Litwin

Institutions: Albert Einstein College of Medicine, Montefiore Medical Center, LabCorp (United States)

Language: English

Topic: Hepatitis C virus research

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,053