The Influence of Treatment with Pegylated Interferon-Alfa
and Ribavirin on Neutrophil Function and Death
in Patients with HIV/HCV Coinfection
Elzbieta Jablonowska,1Kamila Wojcik,1and Marek Nocun2
In patients with human immunodeficiency virus (HIV) as well as in patients with hepatitis C virus (HCV)
infection the impairment of neutrophil activity is observed. We decided to analyze how treatment with pegy-
lated interferon-alfa (Peg-IFN-alfa) and ribavirin affects neutrophil function in HIV/HCV coinfected patients.
The study group consisted of 18 patients with HIV/HCV coinfection, on combination antiretroviral treatment
(cART), aged between 27 and 42y (mean 33.1–4.5y). At the beginning of treatment with Peg-IFN-alfa and
ribavirin all patients had an undetectable HIV viral load, and CD4 T-cell counts higher than 350cells/lL. At two
time points, before and after 12wk of treatment with Peg-IFN-alfa and ribavirin, we examined intracellular
levels of reactive oxygen species (ROS), and expression of selected adhesion molecules on whole blood neu-
trophils, along with apoptosis and necrosis of these cells. These analyses were done with flow cytometry. During
anti-HCV therapy undetectable HIV levels were maintained in all patients. Treatment with PEG-IFN-alfa and
ribavirin resulted in increases in the expression of CD11b and CD18, and decreases of CD16 and CD62L.
However, only the change in CD62L expression was statistically significant (p<0.05). Moreover, the treatment
resulted in increased apoptosis of neutrophils, while necrosis remained unchanged. After 12wk of treatment, an
increase in ROS production by neutrophils stimulated with PMA was observed (p<0.01). In HIV/HCV coin-
fected patients on cART, PEG-IFN-alfa and ribavirin treatment caused an activation of neutrophil function, yet it
did not affect the suppression of HIV replication.
infected with hepatitis C virus (HCV) via the same route of
transmission (24,26). It is well known that the prognosis of
individuals with coinfection is worse than in HCV mono-
infected patients. In coinfected patients progression of liver
fibrosis occurs more rapidly, and patients are more likely to
develop liver cirrhosis and liver carcinoma (1,18). Also, the
response to treatment with pegylated-interferon-alfa (Peg-
IFN-alfa) and ribavirin in coinfected patients is not as good as
in individuals infected with HCV alone (16). Antiviral treat-
ment with Peg-IFN-alfa and ribavirin eliminates HCV in less
than half of coinfected patients (22,28).
Interferon-a (IFN-a) displays antiviral, immunoregulatory,
and antiproliferative activity (23,27). This cytokine stimulates
transcriptional activation of hundreds of genes with antiviral
n Europe and the U.S., about one-third of human
immunodeficiency virus (HIV)-positive people are co-
efficacy. IFN-a enhances production of reactive oxygen spe-
cies (ROS), increases expression of adhesive molecules, and
participates in the regulation of apoptosis (2,4,19). Being the
key second messengers, ROS are involved in numerous sig-
naling pathways, and they modulate phagocytosis, secretion,
gene expression, and apoptosis (10). Augmented ROS pro-
duction in patients with chronic hepatitis C can contribute to
the inhibition of HCV replication and thus to the elimination
of HCV (6). However, excessive ROS production can cause
hepatocyte injury (7,9).
In a previous study we observed that as a result of treat-
ment with IFN-a and thymus factor X (TFX), the formation of
free oxygen radicals by resting (unprimed) neutrophils in-
creased both without stimulation and following stimulation
by N-formyl-methionyl-leucyl-phenylalanine (fMLP). Along
with these changes, a compensatory increase in serum anti-
oxidative capacity was observed (14). We decided to ana-
lyze the effect of Peg-IFN-alfa and ribavirin treatment on
1Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland.
2Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland.
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ª Mary Ann Liebert, Inc.
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Address correspondence to:
Dr. Elzbieta Jablonowska
Department of Infectious Diseases and Hepatology
Medical University of Lodz
Received October 23, 2011; accepted December 13, 2011.
172JABLONOWSKA ET AL.