Protease inhibitors partially overcome the interferon nonresponse phenotype in patients with chronic hepatitis C

A. Duarte-Rojo, S. E. Fischer, O. Adeyi, D. Zita, M. G. Deneke, N. Selzner, L. Chen, M. Malespin, S. J. Cotler, I. D. McGilvray, J. J. Feld

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Abstract

The outcome of triple therapy with protease inhibitors (PI) depends on the intrinsic response to interferon. Interferon-stimulated gene (ISG) expression differs by cell type in the liver and is a strong predictor of interferon responsiveness. Patients who respond well to interferon have low/absent ISG expression in hepatocytes but significant ISG expression in macrophages. Nonresponders (NRs) show the opposite pattern. We aimed to determine the association between cell-type-specific ISG staining and treatment outcome with PI-based triple therapy. Liver biopsy tissue from consecutive patients treated with boceprevir or telaprevir with peginterferon and ribavirin was stained for myxovirus A (MxA). Staining was scored 0-3 in macrophages (M-MxA) and hepatocytes (H-MxA), and IL28B genotyping was performed. Of 56 patients included 41 achieved SVR (73%) (sustained virological response), 2 (4%) relapsed, 10 (18%) were NRs, and 3 (5%) were lost to follow-up. Median M-MxA staining was stronger and H-MxA staining was weaker in patients who achieved SVR. MxA staining correlated with IL28B genotype and with the HCV RNA decline during lead-in phase. However, unlike with dual therapy, the negative predictive value (NPV) of absent or weak M-MxA staining was poor (42%), while the positive predictive value improved (93%). Although by multivariable logistic regression M-MxA staining was significantly associated with SVR (OR 4.35, 1.32-14.28, P = 0.012), the predictive ability was inadequate to withhold therapy. The interaction between macrophages and hepatocytes plays a critical role in interferon responsiveness; however, the addition of a PI at least partially overcomes the interferon nonresponse phenotype making the predictive ability of ISG staining less clinically useful.

Original languageEnglish (US)
Pages (from-to)340-347
Number of pages8
JournalJournal of Viral Hepatitis
Volume23
Issue number5
DOIs
StatePublished - May 1 2016
Externally publishedYes

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Keywords

  • boceprevir
  • interferon-lambda
  • interferon-stimulated genes
  • myxovirus A protein 1
  • peginterferon
  • telaprevir

Cite this

Duarte-Rojo, A., Fischer, S. E., Adeyi, O., Zita, D., Deneke, M. G., Selzner, N., Chen, L., Malespin, M., Cotler, S. J., McGilvray, I. D., & Feld, J. J. (2016). Protease inhibitors partially overcome the interferon nonresponse phenotype in patients with chronic hepatitis C. Journal of Viral Hepatitis, 23(5), 340-347. https://doi.org/10.1111/jvh.12494