Defective synthesis of granulocyte-colony stimulating factor in pegylated interferon-alpha treated chronic hepatitis C patients with declining leukocyte counts

Background: Pegylated-interferon-alpha (peg-IFN-alpha) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-alpha treatment. Methods: A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start. Results: CHC patients had a significantly lower pre-treatment neutrophil count (3,256 +/- 1,197 versus 3,804 +/- 859; P=0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 +/- 6.2 versus 19.4 +/- 7.5; P=0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r=-0.2; P=0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-alpha treatment, despite declining neutrophil counts. Conclusions: The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-alpha, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-alpha-induced neutropaenia.