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

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.

Fig 1. Flow diagram of the study progress.

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.