TY - JOUR
T1 - Prevalence and impact of baseline resistance-associated substitutions on the efficacy of ledipasvir/sofosbuvir or simeprevir/sofosbuvir against GT1 HCV infection
AU - Wang, Gary P.
AU - Terrault, Norah
AU - Reeves, Jacqueline D.
AU - Liu, Lin
AU - Li, Eric
AU - Zhao, Lisa
AU - Lim, Joseph K.
AU - Morelli, Giuseppe
AU - Kuo, Alexander
AU - Levitsky, Josh
AU - Sherman, Kenneth E.
AU - Frazier, Lynn M.
AU - Ramani, Ananthakrishnan
AU - Peter, Joy
AU - Akuskevich, Lucy
AU - Fried, Michael W.
AU - Nelson, David R.
N1 - Funding Information:
We thank all patients who participate in the HCV-TARGET study and the staff of the Clinical and Data Coordinating Centers and the HCV-TARGET Investigative sites. Funding to support sequencing was provided by Janssen Scientific Affairs and a collaborative agreement with Monogram Biosciences. HCV-TARGET is an investigator-initiated study jointly sponsored by The University of Florida, Gainesville, FL (PI: Nelson), and The University of North Carolina at Chapel Hill, Chapel Hill, NC (PI: Fried) and is funded in part by AbbVie, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Kadmon, and Merck. The author MWF is funded in part by NIH Mentoring Award K24 DK066144. DRN is funded in part by the National Center for Advancing Translational Sciences grant UL1TR001427.
Funding Information:
Competing Interests: GPW discloses research grant funding from the NIH, Department of Defense, Ocean Spray Cranberries, and Abbvie. NT discloses institutional grant funding from Gilead, BMS, AbbVie, NIH, and Merck; consultant work for Gilead and Merck; lectures for CCO Hepatitis, Practice Point Communications, Focus Medical Communications, and Annenberg Center for Health Sciences, PRIME Education Inc. JDR discloses stock from laboratory Corporation of America Holdings, along with employment at Monogram Biosciences and Laboratory Corporation of America Holdings. LL has nothing to disclose. EL has nothing to disclose. LZ has nothing to disclose. JKL discloses institutional grant funding from BMS, Genfit, Gilead, Hologic, Intercept, and Prometheus (all to institution) along with consultant work for AbbVie, BMS, & Gilead. GM discloses institutional grant funding from AbbVie, BMS, Gilead, Merck, Janssen, Vertex, Idenix, Conatus, and Salix. AK discloses institutional grant funding from Gilead along with lecturing for Gilead. JL discloses institutional grant funding from Novartis along with lectures Gilead and Novartis, along with stock in Transplant Genomics Incorporated. KES discloses institutional grant funding from AbbVie, BMS, Gilead, Innovio, Merck, and MedImmune along with consultant work for Medimmune and Viiv; Royalties from U.S. Army and UpToDate; other disclosures from DSMB: MedPlace and SynteractHCR. LMF discloses institutional grant funding and consultant work from Gilead, AbbVie, Janssen, and Merck. AR discloses sponsored lectures from Gilead Sciences and Allergan. JP has nothing to disclose. LA has nothing to disclose. MWF discloses institutional grant funding from Abbvie, Bristol Myers Squibb, Gilead, and Merck along with consultant work for Abbvie, Bristol Myers Squibb, Gilead, Merck, and TARGET PharmaSolutions. MWF also discloses stockholding from TARGET PharmaSolutions and other disclosures from Research grants from NIH. DRN discloses institutional grant funding from AbbVie, Gilead, BMS, Janssen, and Merck along with stockholding from TARGET PharmaSolutions.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2-4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.
AB - Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2-4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.
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U2 - 10.1038/s41598-018-21303-2
DO - 10.1038/s41598-018-21303-2
M3 - Article
C2 - 29453451
AN - SCOPUS:85042216290
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 3199
ER -