Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes

Walter Spindelboeck, Angela Horvath, Monika Tawdrous, Bianca Schmerböck, Gabriele Zettel, Andreas Posch, Andrea Streit, Petra Jurse, Sandra Lemesch, Martin Horn, Gerit Wuensch, Philipp Stiegler, Rudolf E Stauber, Bettina Leber, Vanessa Stadlbauer, Walter Spindelboeck, Angela Horvath, Monika Tawdrous, Bianca Schmerböck, Gabriele Zettel, Andreas Posch, Andrea Streit, Petra Jurse, Sandra Lemesch, Martin Horn, Gerit Wuensch, Philipp Stiegler, Rudolf E Stauber, Bettina Leber, Vanessa Stadlbauer

Abstract

First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival.

Trial registration: ClinicalTrials.gov NCT02545335 NCT02545400.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Flow diagram of the study…
Fig 1. Flow diagram of the study progress.
Fig 2. Characteristics of neutrophils in patient…
Fig 2. Characteristics of neutrophils in patient groups and healthy controls.
Phagocytic capacity of neutrophils (a), proportion of inactive neutrophils (b) and PMN elastase levels per 106neutrophils (c) of patients and controls. Ctrl: healthy controls; TPV: telaprevir group; BOC: boceprevir Group; P/R: Dual therapy with peginterferon/ribavirin; B: baseline; 4w: 4 weeks of therapy; 12w: 12 weeks of therapy; F: follow up a: p = 0.021 vs Ctrl; b: p = 0.010 vs Ctrl.

References

    1. Razavi H, Waked I, Sarrazin C, Myers RP, Idilman R, Calinas F, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm. J Viral Hepat. 2014;21 Suppl 1:34–59. 10.1111/jvh.12248 .
    1. Heim MH. 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol. 2013;13(7):535–42. 10.1038/nri3463 .
    1. Pawlotsky JM, Aghemo A, Dusheiko G, Forns X, Pouti M, Sarrazin C. EASL Recommendations on Treatment of Hepatits C 2014. EASL Office, 7 rue Daubin, 1203 Geneva, Switzerland; 2014.
    1. Poordad F, McCone J Jr., Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195–206. 10.1056/NEJMoa1010494
    1. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16. 10.1056/NEJMoa1012912 .
    1. Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC)—NCT01514890. J Hepatol. 2013;59(3):434–41. 10.1016/j.jhep.2013.04.035 .
    1. Londono MC, Perello C, Cabezas J, Canete N, Lens S, Marino Z, et al. The Addition of a Protease Inhibitor Increases the Risk of Infections in Patients with Hepatitis C-Related Cirrhosis. J Hepatol. 2014. 10.1016/j.jhep.2014.09.025 .
    1. Soza A, Labbe P, Arrese M, Riquelme A, Barrera F, Benitez C, et al. Mycobacterium abscessus pulmonary infection during hepatitis C treatment with telaprevir, peginterferon and ribavirin. Ann Hepatol. 2015;14(1):132–6. .
    1. Hametner S, Monticelli F, Kern JM, Schofl R, Ziachehabi A, Maieron A. Tuberculous sepsis during antiviral HCV triple therapy. J Hepatol. 2013;59(3):637–8. 10.1016/j.jhep.2013.05.005 .
    1. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, et al. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother. 2008;52(12):4432–41. 10.1128/AAC.00699-08
    1. White PW, Llinas-Brunet M, Amad M, Bethell RC, Bolger G, Cordingley MG, et al. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob Agents Chemother. 2010;54(11):4611–8. 10.1128/AAC.00787-10
    1. Njoroge FG, Chen KX, Shih NY, Piwinski JJ. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res. 2008;41(1):50–9. 10.1021/ar700109k .
    1. European Association for Study of L. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60(2):392–420. 10.1016/j.jhep.2013.11.003 .
    1. Sarrazin C, Berg T, Cornberg M, Dollinger M, Ferenci P, Hinrichsen H, et al. [Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C]. Z Gastroenterol. 2012;50(1):57–72. 10.1055/s-0031-1282015 .
    1. Ridruejo E. Safety of direct-acting antivirals in the treatment of chronic hepatitis C. Expert opinion on drug safety. 2014;13(3):307–19. 10.1517/14740338.2014.884068 .
    1. Park C, Jiang S, Lawson KA. Efficacy and safety of telaprevir and boceprevir in patients with hepatitis C genotype 1: a meta-analysis. J Clin Pharm Ther. 2014;39(1):14–24. 10.1111/jcpt.12106 .
    1. Maasoumy B, Port K, Deterding K, Honer Zu Siederdissen C, Markova AA, Rogalska-Taranta M, et al. Limited effectiveness and safety profile of protease inhibitor-based triple therapy against chronic hepatitis C in a real-world cohort with a high proportion of advanced liver disease. Eur J Gastroenterol Hepatol. 2014;26(8):836–45. 10.1097/MEG.0000000000000121 .
    1. Coppola N, Pisaturo M, Sagnelli C, Sagnelli E, Angelillo IF. Peg-interferon Plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors. PLoS One. 2014;9(4):e94542 10.1371/journal.pone.0094542
    1. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417–28. 10.1056/NEJMoa1013086 .
    1. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207–17. 10.1056/NEJMoa1009482
    1. Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, Davies NA, et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology. 2007;46(3):831–40.
    1. Horvath A, Leber B, Lemesch S, Stiegler P, Stauber R, Fickert P, et al. Increased gut permeability, elevated endotoxin related proteins and neutrophil dysfunction in liver cirrhosis. J Hepatol. 2013;58, Supplement 1:104–5.
    1. Calleja J, Pascasio J, Antoran BR, Gea F, Barcena R, Larrubia J, et al. Safety and Efficacy of Triple Therapy With Peginterferon, Ribavirin, and Boceprevir Within an Early Access Program in Spanish Patients with Hepatitis C Genotype 1 with Severe Fibrosis: SVRw12 Analysis. Liver Int. 2014. 10.1111/liv.12656 .
    1. Tawadrous GA, Aziz AA, Amin DG, Eldemery A, Mostafa MA. RANTES, TNF-alpha, oxidative stress, and hematological abnormalities in hepatitis C virus infection. J Investig Med. 2012;60(6):878–82. 10.231/JIM.0b013e318254519e .
    1. Stadlbauer V, Mookerjee RP, Wright GA, Davies NA, Jurgens G, Hallstrom S, et al. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol. 2009;296(1):G15–22. 10.1152/ajpgi.90512.2008
    1. Striki A, Manolakopoulos S, Deutsch M, Mela M, Kalafateli M, Schini M, et al. Cirrhosis but not neutropenia is associated with the development of infection in patients with chronic hepatitis C undergoing treatment with pegylated interferon-alpha and ribavirin. J Viral Hepat. 2014;21(9):624–32. 10.1111/jvh.12197 .
    1. Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology. 2002;36(5):1273–9. 10.1053/jhep.2002.36502 .
    1. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol. 1996;24(1):38–47. .
    1. Meyer-Hoffert U. Neutrophil-derived serine proteases modulate innate immune responses. Front Biosci (Landmark Ed). 2009;14:3409–18. .
    1. Satake K, Carballo J, Appert HE, Howard JM. Elastase activity in pancreatic juice and plasma of the dog. Arch Surg. 1972;104(1):64–8. .
    1. Leber B, Mayrhauser U, Rybczynski M, Stadlbauer V. Innate immune dysfunction in acute and chronic liver disease. Wiener klinische Wochenschrift. 2009;121(23–24):732–44. 10.1007/s00508-009-1288-2
    1. Leber B, Tripolt NJ, Blattl D, Eder M, Wascher TC, Pieber TR, et al. The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study. Eur J Clin Nutr. 2012;66(10):1110–5. 10.1038/ejcn.2012.103 .

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe