STUDY OF THE HEPATITIS C VIRUS
IN THE REPUBLIC OF MACEDONIA
Kiprijanovska S1, Sukarova-Stefanovska E1, Noveski P1,
Chalovska V2, Polenakovic M1, Plaseska-Karanfilska D1,*
*Corresponding Author: Professor Dr. Dijana Plaseska-Karanfilska, Research Centre for Genetic
Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Sciences and Arts, Krste
Misirkov 2, Skopje 1000, Republic of Macedonia; Tel: +389(0)2 3235410; Fax: +389 (0)2 3115434; E-mail:
dijana@manu.edu.mk
page: 67
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INTRODUCTION
Hepatitis C virus (HCV) is a major health problem
affecting 170 million people worldwide. The
prevalence rate is about 1.0% in western countries
and North America, 3.0-4.0% in some Mediterranean
and Asian countries and up to 10.0-20.0% in parts
of central Africa [1]. The HCV infection is the leading
cause of chronic hepatitis worldwide, progressing
to liver cirrhosis, and hepatocellular carcinoma
in approximately 20.0% of patients [2-5].
Hepatitis C virus was the first virus discovered
by molecular cloning [6]. Hepatitis C virus is an
enveloped, positive-sense RNA virus, belonging
to the Hepacivirus genus of the Flaviviridae family
[6]. The genome is approximately 9.6 kb in size and contains an open reading frame (ORF) encoding
a large protein precursor [7]. This precursor is
cleaved by host and viral proteases into various
structural and non structural proteins. The structural
proteins are at the 5’ end and include the capsid
or core protein (c), two envelope proteins (E1 and
E2) and a small protein of unknown function (P7).
The structural proteins are followed by at least six
non structural (NS) proteins denoted as NS2, NS3,
NS4A, NS4B, NS5A and NS5B [8].
On the basis of phylogenetic analysis of nucleotide
sequences, HCV can be divided into six genotypes
and several subtypes. The six genotypes differ
between each other in 30.0-35.0% of sequence,
while the subtypes differ in 20.0-25.0% over the
complete genome. Different HCV genotypes exhibit
different epidemiological and clinical implications.
The HCV genotypes 1, 2, and 3 appear to
have a worldwide distribution. The HCV genotypes
1 and 3 are the most common genotypes in the
United States [9] and in Europe [10,11]. Genotype
3, which is endemic in Southeast Asia, has been encountered
in Europe and the USA, with relatively
high frequency in intravenous (IV) drug users [12].
The HCV genotype 4 appears to be prevalent in
North Africa and the Middle East [13,14], and genotype
5 predominates in South Africa. Genotype 6,
according to different authors, is divided into additional
genotypes 7-11 and is mainly found in the
HCV populations of Vietnam and Hong Kong [15-
19]. Hepatitis C virus genotypes have proved to be
important epidemiologic marker that can be used to
predict success of therapy. The HCV genotype 1 is
a more aggressive strain and one that is less likely
to respond to interferon treatment than HCV genotypes
2 or 3. All this information has great significance
when planning future strategies for eradication
and therapeutic management of HCV.
Molecular detection and characterization of the
HCV infections in the Republic of Macedonia started
in 1990. Since then, more than 4000 samples have
been analyzed at the Research Centre for Genetic
Engineering and Biotechnology (RCGEB) “Georgi
D. Efremov,” Skopje, Republic of Macedonia. Blood
samples were collected by the Clinic of Infection
Diseases, Clinic of Gastroenterology and several
dialysis centers from the Republic of Macedonia.
Amplicor Specimen Preparation and Amplification
kit (Roche Diagnostics, Indianapolis, IN, USA)were used for RNA isolation and amplification according
to the manufacturer’s recommendations.
The prevalence of HCV infections in the healthy
population of the Republic of Macedonia was found
to be 0.4%, while in different at-risk groups of patients
such as IV drug users, hemodialysis patients,
patients under a blood transfusion regimen and
those with unknown factors, the prevalence of HCV
varies between 23.0 and 43.0% [20].
Genotyping analyses were performed on 1346
patients with a positive HCV-RNA analysis result.
The HCV/RNA genotyping was performed with an
in-house allele-specific oligonucleotide (ASO) hybridization
method using specific oligonucleotide
probes for different HCV genotypes [genotype 1
(5’-CGC TCA ATG CCT GGA GAT-3’); HCV2a
(5’-CAC TCT ATG CCC GGC CAT-3’), HCV2b
(5’-CAC TCT ATA CCC GGC CAT-3’), HCV3 (5’-
CGC TCA ATA CCC AGA AAT-3’) and HCV4a
(5’-CAC TCT ATG CCC GGC C-3)].
Genotypes 1 and 3 are predominant in patients
from the Republic of Macedonia. Genotype 1 was
found in 55.4% of genotyped patients (n = 714),
while genotype 3 was found in 44.6% of genotyped
patients (n = 632) [20]. There was statistically significant
difference between the risk factors analyzed
and the acquisition of HCV infection.
Hepatitis C virus is a highly prevalent infection
in chronic dialysis patients (37.7%) and represents
one of the major problems of hemodialysis units
in our country [21]. Genotype 1 is predominant in
this group of patients (90.7%). A combined infection
(4.6%) of genotypes 2 and 3 was found in two
patients (4.6%), and a combined infection of genotypes
1 and 3 was also found in another two patients
(4.6%) [22].
We found predominance of HCV genotype
3 in HCV-positive IV drug users (93.35%). High
prevalence of genotype 3 in an analyzed group of
IV drug users is similar to the pattern of genotypes
in IV drug users in both Europe and the USA [12].
The HCV genotype distribution in our patients over
the years, shows a shift between the prevalence of
genotypes 1 and 3. The increase of patients with
genotype 3 is due to the increasing number of IV
drug users analyzed at our center.
Evidence from several studies indicate that interferon
signaling pathway genes (IPGs) and interferon
stimulated genes (ISGs) are associated with the host response to HCV infection. In order to investigate
the possible association of six polymorphisms
in the OASL-like interferon stimulated gene
with a sustained virological response, we studied six
single nucleotide polymorphisms in the OASL gene
in two groups of patients with an HCV infection:
patients who were non responders to the therapy,
and those who had sustained a virological response
to the therapy. Our preliminary results suggest that
non ancestral alleles in four of the six studied polymorphisms
in the OASL gene are associated with
sustained virological response to pegylated interferon
a-2a (Peg-IFN-a) plus ribavirin therapy [23].
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