|Year : 2018 | Volume
| Issue : 3 | Page : 416-421
Changes in hepatitis C virus genotype distribution in chronic hepatitis C infection patients
Mehmet Burak Selek1, Orhan Baylan1, Ergenekon Karagöz2, Mustafa Özyurt3
1 Department of Medical Microbiology, Sultan Abdülhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
2 Department of Infectious Diseases, Fatih Sultan Mehmet Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
3 Department of Medical Microbiology, Medical Faculty, Istanbul Bilim University, Istanbul, Turkey
|Date of Web Publication||14-Nov-2018|
Dr. Mehmet Burak Selek
Department of Medical Microbiology, Sultan Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul
Source of Support: None, Conflict of Interest: None
Purpose: Identification of hepatitis C virus (HCV) genotypes is very important in the selection of antiviral treatment, dose adjustment of antiviral agents, determining the treatment duration and following-up of treatment response. We aimed to determine the distribution pattern of HCV genotypes in chronic hepatitis C infection (CHC) patients. Materials and Methods: We have included 106 CHC patients who were positive in the anti-HCV and HCV-RNA tests performed in our hospital during the 16-month period. Anti-HCV assays were performed on device using a chemiluminescent microparticle immunoassay, while HCV-RNA tests and HCV genotyping assays were performed by real-time polymerase chain reaction. Results: Of the 106 cases; genotype 1b was detected in 67.0%, genotype 3 was detected in 16.0%, genotype 1a was detected in 14.2% and genotype 2 was detected in 2.8% patients. Genotypes 4, 5 and 6 were not detected in our study group. There were no statistically significant differences between the gender and age groups according to the HCV genotype distribution. The genotype 3 detection rate (16%) was the highest rate among the studies compared with the other studies in our country. Conclusions: Events that cause social changes such as war and immigration and intense commercial and touristic activities affect and alter the HCV genotype distribution in HCV-infected patients. For this reason, further multicentre studies are required reflecting all the regions in order to determine the genotype distribution in HCV-infected patients at regular intervals.
Keywords: Chronic hepatitis C, genotyping, hepatitis C virus
|How to cite this article:|
Selek MB, Baylan O, Karagöz E, Özyurt M. Changes in hepatitis C virus genotype distribution in chronic hepatitis C infection patients. Indian J Med Microbiol 2018;36:416-21
|How to cite this URL:|
Selek MB, Baylan O, Karagöz E, Özyurt M. Changes in hepatitis C virus genotype distribution in chronic hepatitis C infection patients. Indian J Med Microbiol [serial online] 2018 [cited 2019 Oct 21];36:416-21. Available from: http://www.ijmm.org/text.asp?2018/36/3/416/245378
| ~ Introduction|| |
Hepatitis C virus (HCV) is an enveloped, single-stranded RNA virus of positive polarity with about 40–50 nm diameter, belonging to the genus Hepacivirus, family Flaviviridae. The virus causes different acute and clinical manifestations varying from symptomatic to fulminant infections. Infections caused by the HCV virus remain an important public health problem on a global scale, since 1989, when it was described for the first time by Choo et al.,,,,,
According to the latest projections of the World Health Organization, about 3% of the world population, in other words, about 130–300 million people are estimated to be infected with HCV. Patients are generally asymptomatic, 85% of patients develop chronic hepatitis C (CHC) disease, followed by cirrhosis in 20% and hepatocellular carcinoma (HCC) in 1%–4%. It is estimated that on average, 250,000–350,000 CHC patients die annually due to complications such as liver failure, cirrhosis, and HCC.,,,,,,,
It is suggested that the number of active HCV-infected patients in our country is around 500,000 and that the role of HCV in the aetiology of chronic hepatitis and cirrhosis has gradually increased in recent years., The contribution of HCV to chronic hepatitis has increased from 23% to 38.1%, and its contribution to cirrhosis from 25.2% to 45.9% in the last decade. Migrations and mass people displacements, especially in the past half-century due to international travel and trade, have given rise to the concept of an unlimited world. Approximately, 2.3% of the world population is in migration, with an estimated 740 million internal migrants and 232 million international migrants. A total of 1,889,780-registered refugees from various countries, especially from Syria, Iraq, Iran, Afghanistan and Somalia are present in Turkey as of December 2015. This number is much more when the presence of informal immigrants is considered. The high rate of migrations from CHC endemic regions to our country causes an increase in the incidence of this disease and differences in the genotype distribution of HCV.
There are six genotypes and more than 100 subtypes of HCV that are generally recognised today.,,,, Reportedly, the seventh genotype has also been detected in recent years. There are even researchers claiming that there are 11 genotypes of HCV. Whether newly revealed genotypes are subtypes of genotype 6 or new genotypes has not yet been established., There is approximately 35% of nucleotide sequence differences between the genotypes., International HCV genotyping studies have shown that genotypes have geographically different distribution and prevalence around the world and that some genotypes are more dominant in some regions.,
The gold standard method in the identification of HCV genotypes is sequencing of the subgenomic regions of HCV (E1, core, NS5B and 5' UTR). However, polymerase chain reaction (PCR)-restriction fragment length polymorphism, line probe test, PCR and real-time PCR (RT-PCR) carried out with genotype-specific primers are more preferred in the identification of HCV genotypes because of the low costs, resulting in a shorter time, ease of application and requiring fewer devices and materials.,,,,,,,,
The identification of HCV genotypes is very important in selection of antiviral treatment, dose adjustment of antiviral agents, determining the treatment duration, following up of treatment response and prediction of patient prognosis. Genotype is an important indicator of sustained viral response rates. Antigenic differences between the genotypes may cause problems in the serological diagnosis of the infection.,,,
The objective of this study was to determine HCV genotypes in CHC patients who presented to our tertiary Training and Research Hospital in Istanbul Province and were positive in anti-HCV and HCV-RNA tests.
| ~ Materials and Methods|| |
This study included a total of 106 CHC patients who were positive in the anti-HCV and HCV-RNA tests performed in the immunology and molecular microbiology laboratories of the Medical Microbiology Service of our hospital during a 16-month period from 1 January 2015 to 30 April 2016. Age and gender data and HCV genotypes of patients were retrospectively evaluated.
Patients' anti-HCV assays were performed with the Architect SR i2000 (Abbott, USA) device using a chemiluminescent microparticle immunoassay, while HCV-RNA tests and HCV genotyping assays were performed with a 7500 RT-PCR System (Applied Biosystems, USA) using RT-PCR.
HCV-RNA isolation was performed with Magnesia® 2448 Nucleic Acid Extraction and PCR Setup Robotu using Magnesia® 2448 Viral DNA/RNA Extraction Kit (Anatolia Geneworks, Türkiye). The initial volume was applied as 500 μl and the elution volume as 100 μl for the serum samples. Bosphore HCV Quantification Kit (Anatolia Geneworks, Turkey) was used to determine viral loads of the samples after isolation. Genotyping of HCV in samples with a viral load above 100 IU/mL after the quantitation was carried out with Bosphore HCV Genotyping Kit v3 (Anatolia Geneworks, Turkey) in line with the recommendations of the manufacturer. A part of the 5' NS5B region of HCV genome was replicated, and fluorescence was detected using the carboxyfluorescein, cyanine 5 and HEX filters. HCV 1a, 1b, 2, 3, 4, 5 and 6 genotypes were studied with the kit.
Data analysis was performed using frequency analysis and Pearson's Chi-square test with IBM SPSS 20 (IBM Co., Chicago, IL, United States) software. P < 0.05 was considered as statistically significant.
| ~ Results|| |
Out of the 106 patients included in this study, 86 (81.1%) were male and 20 (18.9%) were female. The age range of the patients was between 15 and 80 years with a mean age of 38.6 ± 1.913. While most patients were in 15–30 age range (50 patients; 47.2%), 22 (20.8%) patients were in 31–45 age group, 13 (12.3%) in 46–60 age group and 21 (19.8%) in 61 and over age group.
In our study, genotype 1b was detected in 71 (67.0%), genotype 3 in 17 (16.0%), genotype 1a in 15 (14.2%) and genotype in 3 (2.8%) of CHC patients, whereas genotypes 4, 5 and 6 were not found. Distribution of HCV genotypes by gender and age is presented in [Table 1] and [Table 2]. No statistically significant difference was found between both sexes and age groups in terms of HCV genotype differences (0.361 and 0.09, respectively).
| ~ Discussion|| |
HCV is still a major and serious public health problem today since no vaccine for hepatitis C is available, and prophylaxis with hyperimmunoglobulin is not effective in preventing HCV infection after exposure and actual prevalence of this disease in society is unknown.,, Good understanding of the epidemiology of HCV infection is needed in order to develop strategies to eliminate HCV infection, to build evidence-based health policies and to use the resources rationally. The prevalence of HCV varies worldwide. When countries are grouped according to regions in terms of the incidence of HCV infection, Central and South Asia, North Africa and the Middle East have the highest HCV prevalence.
While interferon and ribavirin treatments given to patients in order to obtain a sustained viral response past 48 weeks in CHC patients infected with genotypes 1 and 4, the treatment duration decreases to 24 weeks in those infected with genotypes 2 and 3, and lower doses of ribavirin are used in these patients.,,, At the same time, the rate of sustained viral response is approximately 80% in genotypes 2 and 3, while the rate of non-response to treatment reaches up to 50%. The rate of sustained viral response in genotype 4 patients is 35%. It has also been reported that patients with genotype 1b have a higher risk of developing cirrhosis and hepatic stellate cell., Although the response of genotype 3 to treatment is better than genotype 1, this genotype is clinically crucial, because it is associated with liver fattening and accelerates the level of liver fibrosis in case of chronic disease, thus initiation of early treatment is important for prognosis. Therefore, HCV genotyping due to all of the above-mentioned reasons is clinically important for the choice of treatment as well as for the prognosis of patients and is helpful for clinicians.,
While genotypes 1, 2 and 3 are widely found all over the world, the distribution of other species differs according to the geographical regions., Globally, the most common HCV genotype is genotype 1, with its subtype is mostly 1b. Genotype 1 accounts for 46% of all HCV infections worldwide. Genotype 1 is more dominant in Australia, Europe, Latin America and North America. Genotype 1a is more frequently reported from North America and Northern Europe; genotypes 2a and 2b from Japan, North America and Europe; genotype 3, especially from India and South and Southeast Asia, Middle East, America, Europe, Australia and Japan and genotype 4, especially from Egypt and from North and Central Africa, Central America and Middle East including Saudi Arabia and Syria; although rarely seen, genotype 5 from South Africa and genotype 6, especially from Hong Kong, Vietnam and other Southeast Asian countries.,,,,, While HCV genotype 3 infections are seen by 30% worldwide, genotypes 2, 4 and 6 are responsible for 23% of all HCV infections. The remaining 1% is caused by the HCV genotype 5 infection. However, it is reported that genotype distributions have changed in patients with coronary heart disease according to countries and geographical regions over the years due to several reasons including wars, forced migrations, facilitated trade and travel opportunities on the world which has become a global village., For example, it is suggested in European studies that there has been a decrease in genotypes 1b and 2, particularly in younger patients and an increase in genotypes 1a, 3 and 4. In Europe, genotype 4 is prevalent, especially among intravenous (IV) drug addicts. IV drug users (IVDUs) and also immigrant number in Turkey has recently increased. In the study conducted by Üçbilek et al., they determined that the most common genotypes among 97 IVDUs are genotypes 3 and 2, whereas genotype 1 was identified with a very low rate. In another study, of the 119 patients, genotype 1 was detected in 71.4% (12.6% genotype 1a, 58.8% genotype 1b), genotype 3 in 16.8%, genotype 2 in 7.6% and genotype 4 in 3.4%. Genotype 5 (5a) (0.8%), which has not been reported previously in Adana, was determined in a Syrian female patient. About 45% of patients who were infected with genotype 3 and 33.3% of patients with genotype 2 infection were IVDUs, and young men (83.3%) constituted the majority of this patient group. In addition, genotype 3 infection was detected in four patients who had a risk for being IVDU with psychiatric disorders and suicide attempt. Amongst 11 Syrian patients with HCV infection, almost all of the infections were associated with medical interventions, the HCV genotypes detected were as follows: 63.6% of genotype 1a, 27.3% of genotype 4 and 9.1% of genotype 5a.
There is no notification and registration system in our country that gives the exact number of HCV infections. Epidemiological data are mostly obtained from the local studies. When studies investigating the distribution of HCV genotypes among CHC patients are examined, genotype 1 appears to be the most dominant (60%–90%) genotype. This genotype is followed by genotypes 3, 2 and 4, but this last ranking may change from study to study. Genotype 1b constitutes 80% of HCV genotype 1 cases. In recent years, genotypes 3 and 4 have more frequently been identified. Some studies performed in our country on this subject are presented in [Table 3].,,,,,,,,,,,,,,,
|Table 3: National Studies Investigating Distribution of Hepatitis C Virus Genotypes|
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Genotype 6 was described in our country for the first time in a study conducted by Tezcan et al. with 236 CHC patients in Mersin in 2013. In that study, genotype 1b was identified by 84.7%, genotype 3a was identified by 4.2%, genotype 1 was identified by 3.8%, mixed type was identified by 2.5% (1a/1b, 2.1%; 2a/2c, 0.4%), genotype 1 was identified by 1.7%, genotype 2 was identified by 1.7%, genotype 4a was identified by 0.8% and genotype 6 was identified by 0.4%. In a study by Çekin et al. conducted in Antalya in 2014, genotype 1 was found in 60.8%, genotype 1a in 12.8%, genotype 3 in 11.5%, genotype 1 in 8.8%, genotype 2 in 4.1%, genotype 3 in 11.5% and genotype 4 in 2% of 148 CHC patients. In a study by Sağlik et al. performed in Antalya in 2014, genotype 1b was identified in 63.3%, genotype 1a in 14.7%, genotype 3 in 11.1%, genotype 1 in 5.4%, genotype 2 in 3.5%, genotype 4 in 1.6% and mixed type in 0.2% (1 + 4 in one patient) in 422 CHC patients. It is noteworthy that unlike the other national studies, genotype 3 was found to be over 10% (11.1% and 11.5%, respectively) in the mentioned two studies performed in Antalya in the same year (2014).
In a study by Borcak et al. conducted in Nevşehir in 2015, genotype 1 was found in 45.1%, genotype 1b in 37%, genotype 2 in 14.5%, genotype 3 in 1.2% and genotype 4 in 0.6% of 170 CHC patients. The rate of genotype 2 (14.5%) in that study was found to be higher, unlike the other studies performed in our countries. The authors attributed this high rate to the fact that Nevşehir Province is a touristic area and that Turkish citizens living abroad visit here at certain times.
In our study, genotype 1 had the highest rate at 81.2% (86/106). Genotype 1 consisted of genotype 1b by 83% (71/86) and genotype 1a by 17% (15/86). Among all genotypes, the rate of genotype 1 was 67% (71/106) and the rate of genotype 1a was 14.2% (15/106). In this study, genotype 1 was followed by genotype 3 (16%, 17/106). It is remarkable that this rate was higher than the rates of genotype 3 reported in the studies that are shown in [Table 3]. We detected genotype 2 only in 3 (2.8%; 3/106) patients. Whereas genotypes 4, 5, 6 and mixed type were not observed.
Abacioglu et al. found that the mean age of patients infected with genotype 1a was lower than those infected with genotype 1b in a haemodialysis group of 45 patients; Altuglu et al. reported that the mean age of patients infected with genotype 1 was significantly higher than those infected with the other types; Tezcan et al. stated that genotypes 1, 1a and 1a/1b show a similar distribution in both males and females, but genotype 1b was found more common in females, and other subtypes out of genotype 1b were more common in males and Sağlik et al. found that the mean age of patients infected with genotype 1 was significantly higher than the mean age of those infected with other genotypes. However, when the national studies that we presented are examined in general, it is understood that there is usually no statistically significant difference between age (4–6, 8, 15, 17, 21 and 35) and gender (4, 5, 8, 9, 17, 20, 21, 31 and 35) in terms of the distribution of genotypes in CHC patients.
Evaluating HCV genotype data reported from various regions in our country, genotype 1b is still the most frequently detected genotype. As is seen in [Table 3], genotypes other than genotype 1b have become more widespread in recent years. However, the different methods and study groups used in these studies make the comparison of obtained data with each other difficult. Events that cause social changes such as war and immigration and intense commercial and touristic activities affect the epidemiology of infections.
In our study, the automated RT-PCR method was used similar to other studies.,,,, This method has several advantages such as being automated, giving results in a short time and being a user independent and standardised system.
In our study, it was determined that the most common genotype in the CHC patients followed up in our hospital was genotype 1b and that genotype 3 had the highest rate (16%) among the studies we could reach in our country. When our genotype 3 detection rate was compared with the national studies shown in [Table 3], it was most similar to the rate reported in the studies that were conducted in Antalya in 2014., İstanbul and Antalya being the leading provinces that attract tourists from the Turkic Republics, Russia and neighbouring countries, where genotype 3 is dominant in recent years may explain the high detection rate of this genotype in our study. Sağlik et al. attributed the high rate of genotype 3 (11.1%) found in their study to that 40.4% of the patients were foreign national, mostly from Russia and neighbouring countries. Kuzin et al. reported that in recent years, the incidence of genotype 3 has increased in CHC patients in Russia. Genotype 3 accounts for 40% of all HCV infections in Asia. In a study by Chakravarti et al. performed in India in 2011, genotype 3 was found in 63.39%, genotype 1 in 30.98% and genotype 2 in 5.63% of 71 CHC patients. In a study by Mahfoud et al. with 28 patients who had a positive HCV-RNA, genotype 3 was found by 57%, genotype 1 by 21%, genotype 4 by 18% and mixed genotype as genotypes 1 + 4 by 4%.
In our study, although patients in the study group were not inquired about where they lived, high incidence of genotype 3 might be due to the influence of the patients who have come from the mentioned endemic countries in terms of HCV infection.
In a meta-analysis, Ghaderi-Zefrehi et al. examined all studies investigating the distribution of HCV genotypes in the Middle East countries and reported that genotype 1 was the most common genotype in Turkey, Israel, Greek-populated Southern Cyprus and Iran (82%, 68%, 68% and 55%, respectively); and genotype 4 in Egypt, Iraq, Saudi Arabia and Syria, which are Arab countries (86%, 60%, 56% and 57%, respectively), and that the most common genotype in the Middle East region was genotype 4 by 74.7%, followed by genotype 1 by 15.1%.
| ~ Conclusion|| |
In our study, it was determined that genotype 3 had the highest rate among the studies we could reach in our country. We believe that this finding may be an important finding indicating that it may be effective in the migration and tourism genotype change. The fact that genotype 4 was not detected or found at very low rates in our study, and other national studies (except the studies performed in Kayseri) suggest that genotype 4 transmission from the Middle East yet does not present any risk. Further multicentre studies are required reflecting all the regions in order to determine the genotype distribution in HCV-infected patients at regular intervals in our country.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]