Abstract
BackgroundTreatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. The duration of treatment required to achieve cure differs between individuals and relapse can occur. We asked whether cellular and transcriptional profiling of peripheral blood collected during treatment could identify biomarkers predictive of treatment outcome.MethodsWe analyzed peripheral blood collected during treatment of genotype 1 HCV with 24 weeks of sofosbuvir and weight-based or low dose ribavirin in a trial in which 29% of patients relapsed. Changes in host immunity during treatment were assessed by flow cytometry and whole blood gene expression profiling. Differences in expression of immune-relevant transcripts based on treatment outcome were analyzed using the Nanostring Human Immunology V2 panel.ResultsMultiple cellular populations changed during treatment, but pre-treatment neutrophil counts were lower and natural post-treatment killer cell counts were higher in patients who relapsed. Pre-treatment expression of genes associated with interferon-signaling, T-cell dysfunction, and T-cell co-stimulation differed by treatment outcome. We identified a pre- and post-treatment gene expression signature with high predictive capacity for distinguishing treatment outcome, but neither signature was sufficiently robust to suggest viability for clinical use.ConclusionsPatients who relapse after hepatitis C virus therapy differ immunologically from non-relapsers based on expression of transcripts related to interferon signaling and T-cell dysfunction, as well as by peripheral neutrophil and NK-cell concentrations. These data provide insight into the host immunologic basis of relapse after DAA therapy for HCV and suggests mechanisms which may be relevant for understanding outcomes with currently approved regimens.
Highlights
SPARE was a trial conducted at the National Institute of Allergy and Infectious Diseases (NIAID) in which patients infected with hepatitis C virus (HCV) genotype-1 were treated with sofosbuvir and weight-based or low dose ribavirin for 24 weeks, as previously described [14, 17]
We had not observed these declines in data from previously published ribavirin-free Direct acting antiviral (DAA) cohorts [16], and suspect they may reflect an impact of ribavirin on overall leukocyte counts, as previously reported [20]
While multiple canonical ISGs decreased during treatment and did not differ by treatment outcome (e.g. CXCL10, RARRES3, MX1), we were intrigued to find that expression of both IFNAR1 and IFNAR2 increased with treatment, suggesting an inverse correlation between type-I receptor expression level and interferon signaling
Summary
Treatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. Over 90% of patients with chronic hepatitis C virus (HCV) infection achieve a sustained virologic response (SVR) after 8–12 weeks of treatment with currently approved direct acting antivirals (DAAs). When 4–6 week courses of treatment are given, treatment failures are unacceptably high. Such failures could relate to drug potency, drug susceptibility of the virus, virus replication levels, and patient adherence, but host factors may play a role [1,2,3,4,5,6]. We hypothesize there is a role for host immunity in modulating, or at least reflecting, the odds of achieving SVR
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