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IFNL4-?G genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin.

ABSTRACT: Response to pegylated interferon-alpha and ribavirin (IFN-?/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-?-free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-?G) bolsters the established association with IFN-?/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-?G is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-?4 in IFN-?-free DAA therapies.

SUBMITTER: Meissner EG

PROVIDER: S-EPMC4017364 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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IFNL4-ΔG genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin.

Meissner Eric G EG Bon Dimitra D Prokunina-Olsson Ludmila L Tang Wei W Masur Henry H O'Brien Thomas R TR Herrmann Eva E Kottilil Shyamasundaran S Osinusi Anuoluwapo A

The Journal of infectious diseases 20131223 11

Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α-free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir al ...[more]

PMID: 24367041

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Project description:ImportanceThe efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.ObjectiveTo determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.Design, setting, and patientsSingle-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).InterventionsIn the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.Main outcomes and measuresThe primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).ResultsIn the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.Conclusion and relevanceIn a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively.Trial registrationclinicaltrials.gov Identifier: NCT01441180.

Project description:The analysis of inflammatory cytokines and chemokines produced during hepatitis C virus (HCV) infection has advanced our understanding of viral-host interactions and identified predictors of treatment response. Administration of interferons (IFNs) made it difficult to interpret biomarkers of immune activation during treatment. Direct-acting antiviral (DAA) regimens without IFN are now being used to treat HCV with excellent efficacy. To gain insight into HCV-host interactions occurring before, during, and after HCV treatment, we performed a case-control study that measured serial plasma levels of IFN-?-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1?), and interleukin-18 (IL-18) in 131 patients with chronic HCV treated with sofosbuvir (SOF) plus ribavirin (RBV). A linear regression analysis using baseline factors identified strong positive associations between elevated alanine aminotransferase and pretreatment IP-10 and between the presence of cirrhosis and elevated pretreatment IL-18. Mean IP-10, MCP-1, MIP-1?, and IL-18 levels all decline on therapy, but display different dynamics late in treatment and after cessation of therapy. On treatment, IP-10 and MIP-1? levels were significantly higher in individuals who achieved sustained virological response (SVR). Logistic regression analyses examining treatment response in all patients demonstrated significant associations between higher baseline MIP-1? levels and smaller decreases in MIP-1? early in treatment and SVR. Higher early MIP-1? levels were also significantly associated with SVR in subsets of patients with cirrhosis and individuals with genotype 3 (GT3) infection, two factors associated with decreased responsiveness to treatment.Changes in IP-10 levels mirror HCV RNA, suggesting that IP-10 is an indicator of innate immune viral recognition. MIP-1? levels remain elevated in GT2/3 patients who achieved SVR, suggesting differential immune activation in those who respond to SOF/RBV therapy and a potential role in predicting treatment responses.

Dataset Information

IFNL4-?G genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin.

Publications

IFNL4-ΔG genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin.

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