Immunological Predictors of Nonresponse to Directly Acting Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis

Kate Childs, Elliot Merritt, Aisling Considine, Alberto Sanchez-Fueyo, Kosh Agarwal, Marc Martinez-Llordella, Ivana Carey, Kate Childs, Elliot Merritt, Aisling Considine, Alberto Sanchez-Fueyo, Kosh Agarwal, Marc Martinez-Llordella, Ivana Carey

Abstract

Background: Sustained virological response rates (SVRs) to directly acting antiviral (DAA) therapy for hepatitis C virus (HCV) are lower in decompensated cirrhosis. Markers of innate immunity predict nonresponse to interferon-based HCV treatment; however, whether they are associated with the response to DAAs in patients with decompensation is not known.

Methods: Information on demographics, adherence, viral kinetics, and resistance were gathered prospectively from a cohort with decompensated cirrhosis treated with 12 weeks of DAAs. C-X-C motif chemokine-10 (CXCL-10) level and T-cell and natural killer (NK) cell phenotype were analyzed pretreatment and at 4 and 12 weeks of treatment.

Results: Of 32 patients, 24 of 32 (75%) achieved SVR (responders). Eight of 32 (25%) experienced relapse after the end of treatment (nonresponders). There were no differences in demographics or adherence between groups. Nonresponders had higher CXCL-10; 320 pg/mL (179461) vs 109 pg/mL (88170) in responders (P < .001) and differential CXCL-10 dynamics. Nonresponders had lower NK cell frequency, higher expression of activation receptor NKp30, and lower frequency of the NK subset CD56-CD16+.

Conclusions: Nonresponders to DAAs displayed a different NK phenotype and CXCL-10 profile to responders. Nonresponders did not have poorer adherence or baseline virological resistance, and this shows that immunological parameters are associated with treatment response to interferon-free treatment for HCV in individuals with decompensated cirrhosis.

Keywords: HCV; cirrhosis; directly acting antiviral; hepatitis C..

© The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
C-X-C motif chemokine-10 ([CXCL-10] pg/mL) change over time by groups: rapid decline in hepatitis C virus (HCV) ribonucleic acid (RNA) (undetectable by week 6 and achieved sustained virological response rate [SVR]), slower HCV RNA decline (undetectable after week 6 and achieved SVR), nonresponder (did not achieve SVR). The * signifies P < .05, the black line shows comparison between groups at a time point, and the gray box shows difference in fold change between groups over time.
Figure 2.
Figure 2.
C-X-C motif chemokine-10 ([CXCL-10] pg/mL) and transforming growth factor (TGF)-β (µg/L) change over time in responders and nonresponders. The * signifies P < .05, the black line shows comparison between groups at a time point, and the gray box shows difference in fold change between groups over time.
Figure 3.
Figure 3.
Natural killer (NK) cell frequency, NKp30-positive NK cells, and NK T-cells (NKT) frequency change over time in responders and nonresponders. The * signifies P < .05, the black line shows comparison between groups at a time point, and the gray box shows difference in fold change between groups over time.
Figure 4.
Figure 4.
CD56bright natural killer (NK), CD56dim NK, CD56−CD16+ NK frequency change over time in responders and nonresponders. The * signifies P < .05, the black line shows comparison between groups at a time point, and the gray box shows difference in fold change between groups over time.
Figure 5.
Figure 5.
Naive CD8, central memory CD8, TEMRA CD8, and T-regulatory (T-reg) cell frequency change over time in responders and nonresponders. The * signifies P < .05, the black line shows comparison between groups at a time point, and the gray box shows difference in fold change between groups over time.

References

    1. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370:1889–98.
    1. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211–21.
    1. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015; 149:649–59.
    1. Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016; 63:1493–505.
    1. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373:2618–28.
    1. Kwo P, Agrawal S. Treating hepatitis C virus in patients with decompensated cirrhosis: why is it so difficult and does a sustained response rate rescue the patient from liver transplantation? Clin Liver Dis 2015; 6:133–35.
    1. Berry L, Irving W. Predictors of hepatitis C treatment response: what’s new? Expert Rev Anti Infect Ther 2014; 12:183–91.
    1. Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV 2015; 2:e319–27.
    1. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017; 66:153–94.
    1. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005; 437:1167–72.
    1. Golden-Mason L, Rosen HR. Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 2013; 255:68–81.
    1. Klenerman P, Thimme R. T cell responses in hepatitis C: the good, the bad and the unconventional. Gut 2012; 61:1226–34.
    1. Teijaro JR, Ng C, Lee AM, et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 2013; 340:207–11.
    1. Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 2008; 105:7034–9.
    1. Oliviero B, Mele D, Degasperi E, et al. Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection. J Hepatol 2013; 59:38–44.
    1. Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 2007; 46:1548–63.
    1. Gozlan Y, Ben-Ari Z, Moscona R, et al. HCV genotype-1 subtypes and resistance-associated substitutions in drug-naive and in direct-acting antiviral treatment failure patients. Antivir Ther 2017. doi: 10.3851/IMP3123.
    1. Wyles D, Dvory-Sobol H, Svarovskaia ES, et al. Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir. J Hepatol 2017; 66:703–10.
    1. Askarieh G, Alsiö A, Pugnale P, et al. Systemic and intrahepatic interferon- gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepatology 2010; 51:1523–30.
    1. Fattovich G, Covolo L, Bibert S, et al. IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C. Aliment Pharmacol Ther 2011; 33:1162–72.
    1. Lagging M, Romero AI, Westin J, et al. IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology 2006; 44:1617–25.
    1. Romero AI, Lagging M, Westin J, et al. Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection. J Infect Dis 2006; 194:895–903.
    1. Duvoux C, Pawlotsky JM, Bastie A, et al. Low HCV replication levels in end-stage hepatitis C virus-related liver disease. J Hepatol 1999; 31:593–7.
    1. Meissner EG, Wu D, Osinusi A, et al. Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Invest 2014; 124:3352–63.
    1. Spaan M, van Oord G, Kreefft K, et al. Immunological analysis during interferon-free therapy for chronic hepatitis C virus infection reveals modulation of the natural killer cell compartment. J Infect Dis 2016; 213:216–23.
    1. Brownell J, Wagoner J, Lovelace ES, et al. Independent, parallel pathways to CXCL10 induction in HCV-infected hepatocytes. J Hepatol 2013; 59:701–8.
    1. Dirchwolf M, Podhorzer A, Marino M, et al. Immune dysfunction in cirrhosis: distinct cytokines phenotypes according to cirrhosis severity. Cytokine 2016; 77:14–25.
    1. Edlich B, Ahlenstiel G, Zabaleta Azpiroz A, et al. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology 2012; 55:39–48.
    1. Gill US, Peppa D, Micco L, et al. Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo. PLoS Pathog 2016; 12:e1005788.
    1. Bozzano F, Picciotto A, Costa P, et al. Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment. Eur J Immunol 2011; 41:2905–14.
    1. Golding A, Rosen A, Petri M, et al. Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses. Immunology 2010; 131:107–17.
    1. Björkström NK, Ljunggren HG, Sandberg JK. CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol 2010; 31:401–6.
    1. Mitchell AM, Stone AE, Cheng L, et al. Transmitted/founder hepatitis C viruses induce cell-type- and genotype-specific differences in innate signaling within the liver. MBio 2015; 6:e02510.
    1. Prenner S, VanWagner LB, Flamm SL, et al. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals [epub ahead of print]. J Hepatol 2017; doi:10.1016/j.jhep.2017.01.020.
    1. Cariani E, Pilli M, Barili V, et al. Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments. Oncoimmunology 2016; 5:e1154249.
    1. Hoechst B, Voigtlaender T, Ormandy L, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50:799–807.
    1. Lawitz E, Flamm S, Yang J, et al. Retreatment of patients who failed 8 or 12 weeks of ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. In: 50th Annual Meeting of the European Association for the Study of the Liver; April 22–26, 2015; Vienna, Austria: EASL—The International Liver Congress.

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