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.
Durante-Mangoni
Emanuele
E
Department of Internal Medicine, Second University of Naples Medical School, Napoli, Italy. emanuele.durante@unina2.it
Iardino
Patrizia
P
Utili
Riccardo
R
Adinolfi
Luigi E
LE
Ruggiero
Giuseppe
G
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood* / Q000627:therapeutic use; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000009:adverse effects*; D011994:Recombinant Proteins
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a