DOI: 10.5061/dryad.x0k6djhnp
title: Ultra-short response-guided Hepatitis C treatment with sofosbuvir and daclatasvir: the SEARCH study HCV sequence data

description: Background WHO has called for research into predictive factors for
 selecting persons who could be successfully treated with shorter durations
 of antiviral therapy for Hepatitis C. We evaluated early virological
 response as a means of shortening treatment and explored host, viral and
 pharmacokinetic contributors to treatment outcome. Methods Duration of
 sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2
 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in
 Vietnam with mild liver disease. Participants received 4 or 8 weeks of
 treatment according to whether D2 HCV RNA was above or below 500 IU/ml
 (standard duration is 12 weeks). Primary endpoint was sustained
 virological response (SVR12). Those failing therapy were retreated with 12
 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at
 baseline, with repeat viral sequencing if virological rebound was
 observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were
 measured on day 0 and 28. Findings Of 52 adults enrolled, 34 received 4
 weeks SOF/DCV, 17 got 8 weeks and one withdrew. SVR12 was achieved in
 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks.
 Overall, 38/51 (75%) were cured with first-line treatment (mean duration
 of 37 days). Despite a high prevalence of putative NS5A-inhibitor
 resistance-associated substitutions (RAS), all first-line treatment
 failures were cured after retreatment (13/13). We found no evidence
 treatment failure was associated with host IFNL4 genotype, viral subtype,
 baseline RAS or DCV levels. SOF metabolite levels were higher in those
 failing 4-week therapy. Interpretation Shortened SOF/DCV therapy with
 retreatment if needed, reduces DAA use while maintaining high cure rates.
 D2 virologic response alone does not adequately predict SVR12 with 4 weeks
 of treatment.
description: At screening, HCV genotype and subtype
 were determined using NS5B, Core and 5’ UTR sequencing, according to the
 method described by Chau et. al. To evaluate the impact of HCV subtypes
 and resistance-associated substitutions on treatment outcome, whole genome
 sequencing (WGS) was additionally performed on all enrolled participants’
 virus at baseline, and upon virological rebound and at start of
 retreatment in participants failing therapy. WGS of the HCV viral genome
 was attained using Illumina MiSeq platform. The de novo assemblies nucleotide
 sequences were translated into amino acid and were aligned to H77 HCV
 reference (GenBank ID: NC_038882.1) and the NS5A and NS5B protein regions
 were extracted.  We only looked for RAS that were present in at least 15%
 of the reads in the sample and had a read count of greater than 10.
 We used the Public Health England (PHE)
 HCV Resistance Group’s definition for resistance-associated substitutions
 (RAS). For
 genotype 1, we looked for RASs defined specifically for genotype 1 as they
 are well studied. For genotype 6, we looked for all RASs defined across
 all genotypes, as little work has been done on RASs in genotype 6.
   For DCV, we looked for 24R,
 28T, 30E/K/T, 31M/V, 32L, 58D, and 93C/H/N/R/S/W in genotype 1 infection
 and additionally looked for 28S, 30R and 31F in genotype 6 infection.
 For SOF, we looked for 159F,
 237G, 282T, 315H/N, 321A/I in genotype 1 infection and additionally looked
 for 289I in genotype 6 infection.   In addition to viral sequencing, we
 evaluated host genetic polymorphisms within the interferon lambda 4
 (<em>IFNL4</em>) gene of all participants at baseline.
 Genotyping of <em>IFNL4</em> rs368234815 was performed on host
 DNA using the TaqMan® SNP genotyping assay and primers described
 previously with
 Type‐it Fast SNP Probe PCR Master Mix (Qiagen).
description: The consensus viral sequences generated by the above method are
 provided in a fasta format data.