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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 997-1004

Study of interferon-γ-inducible protein-10 levels during antiviral therapy of hepatitis C patients with sofosbuvir plus ribavirin and interferon in Menoufia hospitals


1 Department of Microbiology and Immunology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine and Gastroenterology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Microbiology, Chest Hospital, Damanhour, Egypt

Date of Submission12-Oct-2016
Date of Acceptance27-Feb-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Nancy R Ahmed Elhosseny
Chest Hospital, Damanhour, El Beheira Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_555_16

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  Abstract 


Objective
The aim of this work was to study the effect of treatment with sofosbuvir, ribavirin, and interferon on the level of interferon-γ-inducible protein-10 (IP-10) and to determine its role in hepatitis C virus (HCV) patients with liver cirrhosis.
Background
IP-10 is a small cytokine belonging to the CXC chemokine secreted by several cell types in response to interferons (interferon-γ). IP-10 has been attributed to several roles, such as chemoattraction for monocytes, macrophages, T cells, natural killer cells, and dendritic cells, promotion of T cell adhesion to endothelial cells, antitumor activity, and inhibition of bone marrow colony formation and angiogenesis.
Patients and methods
The study was conducted on 27 hepatitis C patients with cirrhosis and 15 age-matched and sex-matched healthy individuals. Serum levels of IP-10 were measured in patients using enzyme-linked immunosorbent assay technique three times: before beginning the treatment, after 1 week of treatment, and finally after 3 months of treatment. IP-10 levels were statistically analyzed in relation to liver cirrhosis and treatment outcome.
Results
IP-10 serum levels were highly elevated in patients when compared with healthy people. Serum IP-10 was significantly higher before beginning HCV treatment and then decreased after 1 week of treatment, and it was markedly decreased after 3 months of treatment.
Conclusion
IP-10 had a fundamental role in the pathogenesis of liver fibrosis and cirrhosis as it was significantly elevated in cirrhotic patients. Furthermore, there was a significant reduction in serum IP-10 concentration following a successful course of HCV treatment.

Keywords: hepatitis C virus, interferon-γ inducible protein-10, sofosbuvir


How to cite this article:
El-Hendawy GR, Salama AA, Elshayb EI, Ahmed Elhosseny NR. Study of interferon-γ-inducible protein-10 levels during antiviral therapy of hepatitis C patients with sofosbuvir plus ribavirin and interferon in Menoufia hospitals. Menoufia Med J 2017;30:997-1004

How to cite this URL:
El-Hendawy GR, Salama AA, Elshayb EI, Ahmed Elhosseny NR. Study of interferon-γ-inducible protein-10 levels during antiviral therapy of hepatitis C patients with sofosbuvir plus ribavirin and interferon in Menoufia hospitals. Menoufia Med J [serial online] 2017 [cited 2018 Sep 19];30:997-1004. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/997/229232




  Introduction Top


Hepatitis C virus (HCV) has been shown to have a worldwide distribution, occurring among individuals of all ages, sexes, races, and regions of the world. HCV affects over 200 million people, with an estimated HCV prevalence of 2.2% globally. It has been estimated that HCV accounts for 27% of cirrhosis and 25% of hepatocellular carcinoma cases worldwide[1].

The global prevalence of HCV varies greatly, and the highest prevalence (15–20%) has been reported in Egypt, which is markedly higher than that in industrialized countries where the prevalence ranges from 0.5 to 2.3%. In Egypt, the major route of exposure to HCV has been through widespread parenteral antischistosomal treatment[2]. Despite the use of oral therapy to treat schistosomiasis, the transmission of HCV in Egypt has continued through a variety of mechanisms, including blood transfusion, injections, dental treatment, surgery, and invasive medical procedures and instrumental delivery[3].

Chemokines (chemotactic cytokines) are a large family of small molecules (8–12 kDa). They are defined by a characteristic three-dimensional structure that is based on two disulphide bridges formed by four conserved cysteine residues. According to the relative position of the two N-terminal cysteine residues, chemokines are divided into four subfamilies: CXC, CC, CX3C, and C. CXC and CC chemokines are the two major subfamilies, with the two N-terminal cysteines being separated by one amino acid or none, respectively. CX3CL1, also known as fractalkine or neurotactin, is the single member of the CX3C subfamily with three amino acids separating the first two cysteine residues. The C subfamily of chemokines is atypical in that it has only one N-terminal cysteine residue[4].

CXCL10 exerts its biological effects by binding to CXCR3, a seven transmembrane-spanning G protein-coupled receptor, in a paracrine or autocrine manner[5]. CXCL10 induction depends predominantly on the carboxyl-terminal region of CXCR3, which is essential for CXCR3 internalization, chemotaxis, and calcium mobilization induced by the CXCL10 ligand. CXCL10 is a pleiotropic molecule capable of exerting potent biological functions, including promoting the chemotactic activity of CXCR3+ cells, inducing apoptosis, and regulating cell growth and proliferation as well as angiogenesis in infectious and inflammatory diseases and cancer[6].

Mechanism of action of sofosbuvir: NS5B is one of the six nonstructural proteins encoded on the HCV genome. It is an RNA-dependent RNA polymerase responsible for replicating the HCV-RNA genome, which is a vital step in the HCV life cycle. The RNA-dependent RNA polymerase exhibits a classic fingers, palm, and thumb structure in which interactions between the finger and thumb subdomains create the catalytic site that ensures the synthesis of positive and negative strands of HCV RNA[7].

The aim of this work was to determine the serum levels of interferon-γ-inducible protein-10 (IP-10) in HCV patients with cirrhosis treated with sofosbuvir, ribavirin (RBV), and interferon with or without previous treatment.


  Patients and Methods Top


Study population and selection of patients

This study was conducted during the period from January 2015 to October 2015 at the Microbiology and Immunology Department, Faculty of Medicine, Menoufia University, in collaboration with Shebin Elkom Fever Hospital, Menoufia Governorate. The study protocol was approved by the local ethics committee of the Menoufia University.

This study involved two groups: group I included 27 hepatitis C patients with cirrhosis (13 male and 14 female), and group II included 15 age-matched and sex-matched healthy individuals (as a control group).

Inclusion criteria

Patients older than 20 years with cirrhosis caused by hepatitis C infection were included in the study.

Exclusion criteria

Patients who had undergone organ transplantation, patients with hepatocellular carcinoma, and patients with other conditions known to be associated with elevated serum IP-10, such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis, were excluded.

Informed consent was taken from both the patient group and the control group before the start of the study.

All participants were subjected to the following:

  1. History taking: personal history and clinical history including hepatic encephalopathy, jaundice, bilharziasis, fever, abdominal pain, ascites, variceal hemorrhage, and associated comorbidities (diabetes and hypertension)
  2. Fibroscanning and abdominal ultrasound to determine the fibrotic stage of the liver
  3. Laboratory investigations at the laboratory of the Shebin Elkom Fever Hospitals. It included the following:


Evaluation of alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transferase, alkaline phosphatase, α-fetoprotein, albumin, and serum bilirubin was carried out using Integra 400 Autoanalyzer (Roche Diagnostics Corporation, Indianapolis, Indiana, USA).

Evaluation of hematological parameters such as red blood cells, white blood cells, and platelets was carried out using autoanalyzer ADVIA 2120 Hematology System (Siemens Healthcare GmbH Henkestr., Erlangen, Germany).

Hepatitis B surface antigen was measured using automated Cobas Amplicor Analyzer (Roche Diagnostic Systems, Tokyo, Japan).

Quantitative PCR for hepatitis C RNA was carried out for each patient four times: before the start of treatment (to confirm the diagnosis of hepatitis C), and then after 1, 3, and 6 months of HCV treatment, respectively.

Measurement of serum IP-10 level was carried out using enzyme-linked immunosorbent assay (ELISA) before the start of treatment, after 1 week, and after 3 months of treatment.

The severity of liver disease was estimated according to model for end-stage liver disease (MELD) score. MELD score was calculated according to the following equation: 9.57 log (creatinine, mg/dl)+3.78 log (bilirubin, mg/dl)+11.2 log international normalized ratio (INR)+6.43, where 6.43 is the constant for liver disease etiology.

Meanwhile, Child–Pugh scoring was carried out based on five variables including ascites, encephalopathy, prothrombin time, and serum levels of bilirubin and albumin. Pugh assigned score ranging from 1 to 3 to each of the variables in the classification. Classes A, B, and C were designated by criteria applied to the sum of the individual score allowing to categorize patients in Child–Pugh grades A (5–6 points), B (7–9 points), and C (10–15 points).

Blood sample collection

Three venous blood samples (5 ml) were drawn under sterile conditions in serum separator tubes from all patients and controls (before treatment, after 1 week, and after 3 months of treatment). After clot formation, blood samples were centrifuged at 1000g for 15 min for serum separation.

Sample preparation and storage

Serum samples were stored in sterile Eppendorf tubes at −20°C in serial numbering as each patient had three samples. Repeated freeze-thaw cycles were avoided.

Quantification of interferon-γ-inducible protein-10 serum levels

Serum IP-10 levels were quantified using Boster's human IP-10 ELISA kits according to the manufacturer's instructions (Boster Biological Technology Co. Ltd, Pleasanton, California, USA). Boster's human IP-10 ELISA kit wasbased on standard sandwich ELISA technology.

Statistical analysis

The data collected were tabulated and analyzed using statistical package for the social sciences software version 20 IBM (International Business Machines Corporation) Armonk, New York, U.S. on IBM compatible computer.

The results were expressed by applying ranges, means ± SD, the c2-test, the Mann–Whitney U-test, t-test, the Kruskal–Wallis test, and P values. A P value less than 0.05 was considered to be significant.

Pearson's correlation was used for normally distributed quantitative variables, whereas Spearman's correlation was used for quantitative variables that were not normally distributed or when one of the variables is qualitative.


  Results Top


The cases included 27 hepatitis C patients (13 male and 14 female) with cirrhosis taking triple therapy (sofosbuvir, ribavirin, and interferon). The mean age of hepatitis C patients was 49.19 ± 11.50 years and that of the control group was 42.93 ± 12.88 years. The incidence of hepatitis C infection was higher in patients aged more than 45 years old, with no statistically significant difference (P > 0.05). Smoking was not a significant risk factor for liver cirrhosis (P > 0.05). No significant difference (P > 0.05) was found between liver cirrhotic patients from rural areas and those coming from urban areas. Liver cirrhosis affects patients of low socioeconomic status more than those of high socioeconomic status with no significant difference (P > 0.05). Moreover, 37% of studied cases were diabetic and 30% were hypertensive [Table 1] and [Figure 1].
Table 1: Demographic characteristics of the studied groups (cases and controls) and patient morbidity

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Figure 1: Co-morbidities among the studied groups of patients. DM, diabetes mellitus.

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There were 18.5% of patients with Child–Pugh class A, 25.9% were of class B, and 55.6% were of class C. About 14.8% of patients had MELD score more than or equal to 30. The majority of patients (40.7%) had MELD score 10–19, whereas 14.9% had MELD score 20–29 and finally 29.6% had MELD score below 9.

Liver and renal functions showed a significant difference between the studied group of cases and controls. There were highly significant differences between cases and healthy individuals as regards serum levels of ALT, AST, alkaline phosphatase, direct serum bilirubin, and α-fetoprotein. Moreover, there was a significant difference between cases and controls as regards serum levels of serum albumin. There were no significant differences between cases and controls as regards urea, creatinine, and γ-glutamyl transferase [Table 2].
Table 2: Comparison between studied groups (cases and controls) as regards hepatorenal laboratory parameters

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There was a highly significant difference between cases and controls as regards prothrombin time (P< 0.001). Moreover, there was a significant difference between cases and controls as regards INR (P< 0.05) [Table 3].
Table 3: Comparison between studied groups (cases and controls) as regards coagulation profile

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IP-10 serum concentrations were significantly higher in patients with liver cirrhosis when compared with healthy individuals (P< 0.001) [Table 4] and [Figure 2].
Table 4: Comparison between studied groups (cases and controls) as regards serum levels of interferon-γ-inducible protein-10

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Figure 2: Comparison between the studied groups (cases and controls) as regards serum levels of interferon-γ-inducible protein-10.

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There was a highly significant difference in the results of the studied cases according to time of drug intake. The highest range (700–2300 pg/ml) of IP-10 with a mean value of 1504.07 ± 436.36 was found before starting treatment, but after 1 week of treatment it was 400–640 pg/ml with a mean value of 492.33 ± 71.88, whereas after 3 months of the treatment it was 100–180 pg/ml with a mean value of 133.52 ± 28.71 [Table 5] and [Figure 3].
Table 5: Effect of sofosbuvir intake on interferon-γ-inducible protein-10 levels in the studied group of cases (n=27)

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Figure 3: Effect of sofosbuvir intake on interferon-γ-inducible protein-10 levels among the studied cases.

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[Table 6] shows that age, sex, residence, occupation, socioeconomic status, and smoking did not influence IP-10 serum concentration. Moreover, there was no significant difference between serum levels of IP-10 pg/ml and patients' comorbidities (P > 0.05) [Figure 4].
Table 6: Relationship between serum levels of interferon-γ-inducible protein-10 in the studied group of cases and their demographic characteristics (n=27)

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Figure 4: Correlation between serum levels of interferon-γ-inducible protein-10 (IP-10) (pg/ml) and PCR in the studied group of cases.

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[Table 4] shows that HCV-RNA PCR was positively correlated with IP-10 serum levels.


  Discussion Top


This study was performed to evaluate the potential role of IP-10 in the pathogenic process of chronic hepatic cirrhosis, and to determine the correlation between IP-10 and the HCV activity and the degree of liver fibrosis. Furthermore, this study aimed to determine the concentration of serum IP-10 before and after antiviral therapy.

In the present study, the mean age of hepatitis C-infected patients was 49.19 ± 11.50 years. This is in agreement with the result of the study conducted by Ruane et al.[8], in Egypt, in which the mean age was 53 ± 12 years. However, a lower mean age was found in the studies conducted by Hajarizadeh et al.[9],[10], in which the mean age was 34 ± 8 and 33 ± 9 years, respectively. This finding may indicate that liver diseases are more commonly encountered in older ages and this can be attributed to the fact that chronic HCV infections generally progress slowly, with limited advanced liver disease in the initial 10–15 years of infection (even in individuals with cofactors for fibrosis progression); thus, the duration of chronic HCV infection and the patient's age are key determinants of morbidity and mortality[11].

There was no significant difference found between hepatitis C-infected patients from rural areas and those coming from urban areas (P = 0.35). However, Lehman et al.[12] stated that HCV prevalence was higher among rural residents than among urban residents (P< 0.0001). This is in line with the parenteral antischistosomal therapy (PAT) hypothesis, which states that rural residents would have a greater burden of schistosomiasis, and therefore greater exposure to parenteral antischistosomal therapy[13].

In this study, there was no significant difference between the two studied groups in relation to their socioeconomic levels. However, in the USA, Scaglione et al.[14] found that the prevalence of chronic hepatitis C was higher in individuals at lower socioeconomic status.

There was a history of cigarette smoking among 33.3% of hepatic patients but without a significant difference between cases and controls. In contrast, Elhawary et al.[15], in Egypt, documented that habitual smoking was a well-documented risk factor for exacerbation of liver conditions, such as increased ALT levels and increased fibrosis. Moreover, Dam et al.[16], in Denmark, stated that smoking was associated with an increased risk for liver cirrhosis independent of alcohol intake [the adjusted hazard ratio of developing alcoholic liver cirrhosis was 2.3 (95% confidence interval: 0.8–6.4) among women who smoked ≤10 g/day, and 3.9 (95% confidence interval: 1.6–9.4) for those smoking >10 g/day (P = 0.001 for trend)]. Hézode et al.[17] reported that nicotine, a major component of tobacco smoke, is mainly metabolized in the liver.

In this study, about 37% of hepatic patients were diabetic. Several studies from different parts of the world found that 13–33% of patients with chronic HCV had diabetes mellitus, mostly type II diabetes mellitus[18]. A study conducted by El Ray et al.[19], in Egypt, showed that, in chronic hepatitis C genotype 4 patients, insulin resistance increased significantly with the fibrosis stage reaching 100% in cirrhotic stage. The pathogenesis of diabetes mellitus in HCV infection may be multifactorial, including abnormal glucose metabolism and insulin resistance, acting in conjunction with undefined pancreatic damage, and occurring in genetically prone patients. Another possible explanation is that β-cell responsiveness is impaired in patients with HCV, possibly because of direct viral effects on β-cell function[15].

In the present study, about 30% of hepatitis C patients were hypertensive. However, Henriksen and Møller[20] stated that the prevalence of arterial hypertension in patients with chronic liver disease (cirrhosis) was much lower (only 3–7%). The same author attributed this to the fact that characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic vascular resistance, high arterial compliance, and resistance to vasopressors.

In the present study, serum levels of ALT and AST were significantly elevated in liver cirrhotic patients (67.48 ± 49.57 IU/l in patients compared with 28.93 ± 11.71 in controls for ALT, and a mean level of 110.66 ± 41.30 IU/l in patients compared with 25.20 ± 7.67 in controls for AST). This result is in agreement with published results of Attallah et al.[21] (mean level 49.20 ± 36.88 IU/l in patients compared with 30.84 ± 10.06 in controls for ALT and mean level 78.04 ± 76.58 in patients compared with 32.44 ± 6.90 in controls for AST). Schuppan and Afdhal[22] attributed these results to leakage of these enzymes from damaged hepatocytes.

In our study, serum bilirubin was significantly elevated in the studied group of patients (P< 0.001). These results are also in agreement with the findings of Attallah et al.[21] and Schuppan and Afdhal[22]. The latter attributed this result to cholestasis, decreased hepatocyte, and renal excretory function.

In the present study, serum albumin, a surrogate marker of liver synthetic capacity, was significantly lower in the hepatic patients (mean level 3.62 ± 1.13 g/dl in patients compared with 4.18 ± 0.52 g/dl in controls). This coincides with the results of Alboraie et al.[23], who documented that fibrosis stage was negatively correlated with albumin [albumin (g/l, mean ± SD) 45.91 ± 3.11 for fibrosis stage 0 (F0), 45.83 ± 3.32 for F1, 44.63 ± 1.99 for F2, 44.62 ± 3.08 for F3, and 40.35 ± 5.95 for F4]. Schuppan and Afdhal[22] attributed the decrease in serum albumin in hepatic patients to the decrease in its production and sequestration into ascites and interstitium (exacerbated in systemic inflammation).

Moreover, in this study, INR was significantly elevated in the studied group of patients (mean level 1.21 ± 0.22 in patients compared with 1.09 ± 0.08 in controls). It is in agreement with the findings of Wiegand and Berg[24], who attributed this result to impaired hepatic biosynthesis of factor V/VII (while thrombin production is maintained).

The present study showed that serum IP-10 was elevated in all patients before their treatment and it was a significantly higher in patients than in controls. This result is in agreement with the study by Barbara et al.[25], who found that IP-10 level was significantly high in HCV-infected patients than in the healthy group. Moreover, a similar result was achieved by Helbig et al.[26], who investigated its expression networks in both chronic HCV infection using microarray analysis to determine chemokine expression in human infection and in chimpanzees that were experimentally infected with HCV.

Moreover, there was an evaluated effect of sofosbuvir intake with ribavirin and interferon on IP-10 levels among the studied cases with a highly significant difference (P< 0.001). The mean value of IP-10 before treatment was 1504.07 ± 436.36; the mean value after 1 week was 492.33 ± 71.88; and the mean value after 3 months was 133.52 ± 28.71. This is in agreement with the findings of Carlin et al.[27], who showed that after initiation of sofosbuvir plus ribavirin, the mean circulating IP-10, MCP-1, MIP-1b, and IL-18 levels decline at varying rates. IP-10, MCP-1, and MIP-1b displayed similar temporal response curves during treatment, characterized by rapidly decreasing levels during week 1 leading to a nadir between week 1 and week 12 on therapy.

In the present study, there was no significant difference between patients' demographic characteristics and serum level of IP-10, where age, sex, residence, socioeconomic status, and smoking did not influence the IP-10 serum concentration. We observed that they were not associated with the systemic IP-10 levels in patients with liver cirrhosis as all had P value more than 0.05. These results are in accordance with those of Kurelac et al.[28], who reported that there was no correlation between serum levels of IP-10 and age and sex. You et al.[29] also stated that there was no significant correlation between serum levels of IP-10 and smoking habit (P > 0.05).

The present study showed that the concentrations of serum IP-10 in CHC patients were positively correlated with the levels of serum HCV-RNA (r = 0.36, P < 0.001). This is in agreement with the findings of Willemse et al.[30], who revealed that the concentrations of serum IP-10 in CHC patients were positively correlated with the levels of serum HCV-RNA (r = 0.81, P < 0.0001).


  Conclusion Top


Chronic hepatitis C patients had significant elevation of serum levels of IP-10 when compared with healthy control. There were significant differences between cases and healthy individuals as regards serum levels of ALT, AST, alkaline phosphatase, direct bilirubin, serum albumin, and α-fetoprotein. Serum IP-10 concentration was significantly reduced with a successful course of triple regimen of antiviral treatment with sofosbuvir, ribavirin, and interferon.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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