|Year : 2017 | Volume
| Issue : 3 | Page : 706-714
Vitamin D receptor polymorphisms as predictors of response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C infection
S Shoeib1, H Zaghla2, S Dina3, M Abd El Hafez1, A Efat1, A El Shormilisy4, R Mohamed MSc 5
1 Department of Internal Medicine, Faculty of Medicine, Mernoufia University, Mernoufia, Egypt
2 Department of Hepatology, National Liver Institute, Mernoufia University, Mernoufia, Egypt
3 Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
4 Department of Internal Medicine, Faculty of Medicine, Helwan University, Helwan, Egypt
5 Department of Internal Medicine, Suez Canal Authority Hospital, Ismailia, Egypt
|Date of Submission||27-Sep-2016|
|Date of Acceptance||02-Dec-2016|
|Date of Web Publication||15-Nov-2017|
Suez Canal Authority Hospital
Source of Support: None, Conflict of Interest: None
The aim of the present study was to assess the influence of polymorphisms in vitamin D receptors (VDRs) Fok1 and Apa1 and interleukin 28B rs12979860 C/T on the response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C.
Vitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus. Genetic polymorphisms affecting the VDR gene have been implicated in several immune disorders.
Patients and methods
This retrospective study was conducted on 80 patients who were divided into two groups: group I – the nonresponders group – comprised 40 patients and group II – the sustained virological response (SVR) group – also comprised 40 patients. The present study also included 20 healthy volunteers as controls. Two single nucleotide polymorphisms in VDRs Fok1 and Apa1 and in IL28B rs12979860 C/T) were determined by real-time PCR and restriction fragment length polymorphisms.
Genotypes of IL28B rs12979860 (CC/CT/TT) were found in 23 (57.5%), 15 (37.5%), and two (5%) patients and of Apa1 (CA/AA/CC) in 24 (60%), 14 (35%), and two (5%) patients. Genotypes of Fok1 (TT/CC/TC) were found in 23 (57.5%), nine (22.5%), and eight (20%) patients, respectively, in the SVR group. Regarding IL28B rs12979860 polymorphisms, patients with a T-allele carrier had higher frequency among nonresponders (87.5%) in comparison with SVR (42.5%). Regarding VDR (Fok1) polymorphisms, patients with a C-allele carrier had higher frequency among nonresponders (92.5%) in comparison with SVR (42.5%). Regarding VDR Apa1 polymorphisms, patients with a C-allele carrier had higher frequency among nonresponders (92.5%) in comparison with SVR (65%).
Pretreatment vitamin D level was significantly higher in responders, and this can be used as a predictor of response to combination therapy for hepatitis C virus. VDR gene polymorphisms (Fok1 and Apa1) and IL28B rs12979860 polymorphism are independently related to response to interferon/ribavirin-based therapy in chronic hepatitis C.
Keywords: hepatitis C virus, predictors of response, vitamin D receptor gene polymorphisms
|How to cite this article:|
Shoeib S, Zaghla H, Dina S, El Hafez M A, Efat A, El Shormilisy A, Mohamed R. Vitamin D receptor polymorphisms as predictors of response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C infection. Menoufia Med J 2017;30:706-14
|How to cite this URL:|
Shoeib S, Zaghla H, Dina S, El Hafez M A, Efat A, El Shormilisy A, Mohamed R. Vitamin D receptor polymorphisms as predictors of response to interferon/ribavirin-based therapy in Egyptians with chronic hepatitis C infection. Menoufia Med J [serial online] 2017 [cited 2019 Nov 12];30:706-14. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/706/218296
| Introduction|| |
Hepatitis C virus (HCV) represents a global problem for public healthcare systems because of its high prevalence and severe health-related complications . HCV is highly prevalent in Egypt, with a predominance of HCV genotype 4 . The standard-of-care (SOC) treatment for chronic HCV was pegylated interferon-α (PEG-IFNα) and oral ribavirin . Because of the significant side-effects and high cost of PEG-IFNα and ribavirin therapy and the relatively long duration of treatment for HCV, it is highly important to identify some molecular markers that can discriminate patients who will not respond to the treatment. Responsiveness to HCV therapy depends on viral factors and host factors. Viral factors, those that are related to HCV virus, include viral genotype and viral load , whereas host factors include sex, age, obesity, insulin resistance, type 2 diabetes mellitus, ethnicity, and genetics such as IL28 polymorphisms . Moreover, vitamin D deficiency is more prevalent in chronic hepatitis C (CHC) patients than in healthy controls. The majority of individuals with CHC are vitamin D deficient . Bitetto et al.  has shown that vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C in liver transplant recipients. Most of the biological activities of activated vitamin D are mediated through a nuclear vitamin D receptor (VDR), which serves as a ligand-activated transcription factor. Polymorphisms within the VDR gene may result in defective gene activation and consecutive impaired effector functions of vitamin D, such as cell differentiation and immune regulation. Lange et al.  detected a correlation between VDR polymorphisms and sustained virological response (SVR) rate in genotype 1, and despite a lack of correlation with serum vitamin D levels the authors suggested that these polymorphisms might be a more precise indicator of the defect in vitamin D metabolism and its consequences on immunity and HCV clearance.
In addition, IL28B gene polymorphism is one of the strongest predictors of SVR. Genome-wide association studies have reported the association between rs12979860 and SVR in patients with genotype 1 . Knowledge of factors predicting sensitivity to combined antiviral treatment is still limited and restricted in populations infected with HCV-4. Therefore, this study aimed to assess the influences of interleukin 28B rs12979860 C/T and VDRs Fok1 and Apa1 polymorphisms on the response to interferon/ribavirin-based therapy in Egyptians with CHC.
| Patients and Methods|| |
This retrospective study assessed stored serum samples of 80 patients with chronic HCV who received PEG-IFN and ribavirin therapy at Interferon Clinic of Tropical Department, Faculty of Medicine, Bny Swief University during the period from July 2010 to July 2012. The present study also included 20 healthy volunteers as controls. Our patients from a previous study provided their informed consent to use their blood and serum samples for this study. Data were retrieved from patient medical records after approval from the ethics committee of the Ministry of Health and Population. Among 80 patients, there were 33 (41.2%) females and 47 (58.7%) males. Responders included 10 (22.7%) females and 30 (53.6%) males aged 39.9 ± 11.7 (mean ± SD) years, and nonresponders included 23 (52.3%) females and 17 (30.4%) males aged 42.5 ± 10.1 (mean ± SD) years.
Each patient received a subcutaneous injection of PEG-IFNα-2a once per week. The dose of IFNα-2a was 180 μg together with oral ribavirin therapy, using 1000 mg/day for those weighing lower to 75 kg and 1200 mg/day for those weighing more than 75 kg in weight. Clinical and demographic characteristics including age, sex, liver biopsy data, HCV viral load, hematological indexes, and biochemistry data were extracted from clinical databases. According to response to therapy, they were classified into two groups. The first group (nonresponders) included 40 patients who did not respond to standard HCV therapy and they did not achieve SVR. The second group included 40 patients who responded to standard HCV therapy and achieved SVR (negative HCV viremia 6 months after stopping therapy). Patients were selected for treatment according to the following criteria: age between 18 and 60 years, white blood cells greater than 4000/mm3, absolute neutrophils greater than 2000/mm3, platelets greater than 85 000/mm3, prothrombin time less than 2 s above the upper limit of normal, direct bilirubin less than 0.3 mg/dl, indirect bilirubin less than 0.8 mg/dl, serum albumin more than 3.5 g/dl, negative HBsAg, antinuclear antibodies less than 1: 40, α-fetoprotein less than 100 IU/ml, and normal serum creatinine, fasting blood sugar, and thyroid stimulating hormone. Patients were excluded if they had comorbid liver disease, autoimmune disease, malignancy, psychiatric diseases, and chronic infection, were on immunosuppressive therapy, were organ transplant recipients, pregnant or breastfeeding women, and evidence of retinal or ischemic heart disease and decompensated liver cirrhosis.
Quantitation of serum level of 25(OH) vitamin D
Serum vitamin D level was detected using an ELISA 25(OH) Vitamin D kit according to the manufacturer's instructions (DRG International Inc., Qiagene, USA). The data are expressed as ng/ml, and normal serum 25(OH) vitamin D level was defined as more than 20 ng/ml.
Total DNA gene was isolated from whole blood mononuclear cells using Qiagene cells/tissue extraction kit (Qiagene, USA) according to the instructions of the manufacturer.
Detection of vitamin D receptor and interleukin 28B polymorphisms
Genomic DNA was extracted from blood samples. The VDR genotype was determined by PCR amplification and restriction length fragment polymorphisms (RFLP). To detect Fok1 polymorphism, a forward primer in exon 2 (5'-AGCTGG CCC TGG CAC TGA CTA TGC TCT-3'; reverse: 5'-ATG GAA ACA CCT TGC TTC TTC TCC CTC-3') was used, and to detect Apa1 polymorphism a forward primer in the intron between exons 8 and 9 (5'-CAG AGC ATG GAC AGG GAG CAA-3'; reverse: 5'-GCA ACT CCT CAT GGC TGA GGT CTC-3') was used. The Fok1 site was detected by PCR (one cycle at 95°C for 5 min, 35 cycles at 69°C for 10 s and 72°C for 15 s, followed by 72°C for 5 min) at a region spanning the site. Amplification originated in exon 2 of Fok1 producing a 265 bp fragment. PCR products (20 μl) were digested by the addition of 5 U Fok1 restriction enzyme and subsequently incubated at 55°C for 2 h. Digestion products were resolved by electrophoresis on 2% agarose gel containing 0.5 μg/ml ethidium bromide. The RFLP were coded as F or f, where the uppercase letter signifies absence and lowercase signifies presence of the restriction site. The genotypes of the recipients were determined by observing the number of bands in the PCR–RFLP digest: homozygote lacking the Fok1 site (FF), one 265 bp band; homozygote containing the Fok1 site (ff), one 196 bp band and one 69 bp band; and heterozygote (Ff), all three sizes of bands were present. Apa1 genotypes were obtained using the same approach as described above, except for the use of the Apa1 restriction enzyme .
IL28B rs12979860 genotyping was detected by the multiplex tetra-primer PCR method. The PCR reaction was performed with 1 μl whole blood, using all four primers [Con forward: 5'-GCTCAGCGCCTCTTCCTCCT-3', Con reverese: TCCCATACACCCGTTCCTGT-3, IL28 (T) forward: 5'-AGGAGCTCCCCGAAGGAGT-3', and IL28 (C) reverese: 5'-TGCAATTCAACCC TGGTACG-3') and direct Taq PCR MasterMix in 20 μl reaction volume. Amplification was carried out by an enzyme activation step for 5 min at 95°C, followed by 35 cycles of 45 s at 95°C, 45 s at 60°C, and 45 s at 72°C, and a final extension for 10 min at 72°C. The amplicons were separated by 2% agarose gel electrophoresis and stained with ethidium bromide (0.5 mg/l). Both homozygous (CC and TT) and heterozygous genotypes (CT) were easily detected on agarose gel .
All collected data were revised for completeness and accuracy. Precoded data were entered into a computer using statistical package of social science software program, version 15, for analyses (SPSS; SPSS Inc., Chicago, Illinois, USA). Data are summarized using mean values and SD for quantitative variables and numbers and percentages for qualitative variable. Comparison between qualitative variables was carried out using χ2-tests, whereas the independent T-test was used for quantitative variables that were normally distributed, and nonparametric Kruskal–Wallis and Mann–Whitney tests were used for quantitative variables that were not normally distributed. Multivariate analysis was carried out for predictors of lack of response using binary logistic regression analysis. P values less than 0.05 were considered statistically significant.
| Results|| |
Among our 80 patients, there was significant difference regarding sex with a higher percentage of nonresponders being females (52.3%) compared with males (30.4%) (P = 0.007), but there was no significant difference regarding age with nearly equal mean values between both groups (P = 0.544) [Table 1].
There was a statistically significant difference in baseline laboratory parameters with higher pretreatment serum total bilirubin, alkaline phosphatase, viral load, random blood sugar, and α-fetoprotein (AFP) among nonresponders than in the SVR group (P < 0.001, <0.001, 0.038, 0.026, and < 0.001, respectively) [Table 2]. There was no statistically significant difference in the degree of hepatic fibrosis between nonresponders and the SVR group [Figure 1]. There was a significant difference regarding vitamin D levels with higher frequency of patients with vitamin D levels less than 20 ng/ml among nonresponders in comparison with the SVR group [Figure 2].
|Figure 1: Results of baseline liver biopsy using the Metavir score system among responders and nonresponders before receiving combination therapy (PEG-IFN/RBV). PEG-IFN, pegylated interferon.|
Click here to view
|Figure 2: Vitamin D levels among nonresponders and sustained virological response before receiving combination therapy (PEG-IFN/RBV). PEG-IFN, pegylated interferon.|
Click here to view
There was a significant statistical difference in VDR Apa1 genotype distribution between nonresponders and responders: the A/A genotype was present in 7.5 versus 35%, the C/A genotype was present in 32.5 versus 60%, and the C/C genotype was present in 60 versus 5% respectively (P < 0.001). In addition, the allele frequencies between the two groups showed that A-allele (wild type) (65%) was more frequent than the C-allele (35%) in the SVR group, whereas the frequency of the C-allele (76.3%) was higher than that of the A-allele (23.7%) among nonresponders [Table 3] and [Figure 3].
|Table 3: Prevalence of single nucleotide polymorphisms in the promoter region of vitamin D receptor gene Apa1 in responders and nonresponders to interferon therapy for chronic hepatitis C and healthy individual|
Click here to view
|Figure 3: Prevalence of single nucleotide polymorphisms in the promoter region of vitamin D receptor gene Apa1 in responders and nonresponders to interferon therapy for chronic hepatitis C and healthy individuals.|
Click here to view
There was a significant statistical difference in VDR Fok1 genotype distribution between nonresponders and responders: the C/T genotype was present in 30% versus 20%, the T/T genotype was present in 7.5% versus 57.5%, and the C/C genotype was present in 62.5% versus 22.5% respectively (P < 0.001). Moreover, the allele frequencies between the two groups showed that T-allele frequency (67.5%) was higher than the C-allele (32.5%) in the SVR group, whereas the frequency of the C-allele (77.5%) was higher than the frequency of the T-allele (22.5%) among nonresponders [Table 4] and [Figure 4].
|Table 4: Prevalence of single nucleotide polymorphisms in the promoter region of vitamin D receptor gene Fok1 in responders and nonresponders to interferon therapy for chronic hepatitis C and healthy individual|
Click here to view
|Figure 4: Prevalence of single nucleotide polymorphisms in the promoter region of vitamin D receptor gene Fok1 in responders and nonresponders to interferon therapy for chronic hepatitis C and healthy individuals.|
Click here to view
There was a significant statistical difference in IL28B rs12979860 genotype distribution between nonresponders and responders: the C/T genotype was present in 35% versus 37.5%, the C/C genotype was present in 12.5% versus 57.5%, and the T/T genotype was present in 52.5% versus 5%, respectively (P < 0.004, <0.001, and < 0.001, respectively). Furthermore, the allele frequencies between the two groups showed that the C-allele (76.3%) was more frequent than the T-allele (23.7%) in the SVR group, whereas the frequency of the T-allele (70%) was higher than the C-allele (30%) among nonresponders [Table 5].
|Table 5: Prevalence of single nucleotide polymorphisms in IL28B rs12979860 genotype in responders and nonresponders to interferon therapy for chronic hepatitis C and healthy individual|
Click here to view
In the univariate analysis, the following variables were statistically significant, with higher significance linked with therapeutic failure: female sex, higher baseline viral load, VDR (Fok1) C-allele carrier, VDR (Apal) C-allele carrier, IL28B rs12979860T allele carrier state, lower vitamin D levels, higher AFP level, and higher random blood sugar [Table 6].
|Table 6: Stepwise backward elimination regression analysis model (multivariate regression analysis)|
Click here to view
These variables were included in the multivariate analysis. Direct logistic regression was performed to assess the effect of a number of factors on patient response to treatment, and the only one found to be significant was vitamin D levels with an odds ratio of 1.731.
| Discussion|| |
HCV represents a global problem for public healthcare systems because of its high prevalence and severe health-related complications . Combination therapy of PEG-IFNα and ribavirin was the SOC therapy . Because of the important side-effects and high cost of PEG-IFN plus ribavirin therapy as well as the relatively long duration and exhaustive course of treatment for HCV, it is highly important to identify some molecular markers that can discriminate patients who will not respond to the treatment. Accordingly, we aimed to detect the effect of single nucleotide polymorphisms of VDR Fok1 rs2228570 T/C and Apa1 rs7975232 C/A and interleukin-28B rs12979860 C/T polymorphisms on SVR to interferon/ribavirin-based therapy in Egyptians with CHC infection. Among 80 patients, there were 33 (41.2%) female and 47 (58.7%) male patients. The responders included 10 (22.7%) female and 30 (53.6%) male patients aged 39.9 ± 11.7 (mean ± SD) years, and the nonresponders included 23 (52.3%) female and 17 (30.4%) male patients aged 42.5 ± 10.1 (mean ± SD) years.
Clearly, in this study, no statistically significant difference regarding age of patients was observed. In disagreement with our finding, Shiffman et al.  noticed that SVR was significantly correlated with patients younger than 40–45 years and showed the best response rates.
Unexpectedly, in our study, the female sex was a poor predictor to response. This is contradictory to Poynard et al. , who showed a significant positive correlation between female sex and SVR,and Kau et al. , who reported that female patients were able to achieve higher SVR rates than males in two studies using the old combination of standard IFN and RBV. In addition, Fried et al.  found a significant negative correlation between male sex and SVR by univariate logistic regression analyses.
This coincides with Esmat et al.  who reported that among baseline factors associated with SVR identified by univariate logistic regression analyses was male sex. We do attribute this result to the low sample size.
Viral load analysis by PCR showed that HCV-RNA levels were significantly lower in the SVR group than in nonresponders; this finding coincides with Shiffman et al. , who showed a low baseline viral load to be an independent predictor of SVR regardless of the genotype. Moreover, Fung et al.  found that low viral load is associated with good virological response in patients treated with PEG-IFN plus ribavirin therapy.
No statistically significant difference in the degree of hepatic fibrosis between the nonresponders and the SVR group was found; this is contradictory to Al-Faleh et al.; Hassan et al.; and Kamal et al. ,,, who reported that low fibrosis stage and absence of cirrhosis are predictors of response to antiviral therapy with PEG-IFN plus ribavirin. In addition, Romero-Gomez  found that the mean fibrosis was lower between responders (1.41 ± 0.88 vs. 2.16 ± 1.39; P = 0.0001). This finding may be explained by the changes in intrahepatic inflammatory response, and mediators during fibrosis progression may affect combined PEG-IFN and ribavirin response .
This coincides with Asselah et al.  who reported no association between fibrosis stage and response to antiviral therapy with PEG-IFN plus ribavirin therapy.
AFP was higher in nonresponders than in the SVR group. This coincides with Males et al. , who reported that higher serum AFP was independently and negatively associated with SVR in Egyptian patients with genotype 4. In addition, other studies have also demonstrated that the presence of AFP was found to predict SVR, and a higher AFP level is associated with negative treatment outcome ,.
We reported significant differences regarding baseline biochemical parameters such as pretreatment serum total bilirubin level, alkaline phosphatase, and random blood sugar, which were significantly higher in nonresponders than in the SVR group; this finding was in contrast with El Makhzangy et al. , who found that there was no impact of pretreatment serum bilirubin levels, alkaline phosphatase, and thyroid stimulating hormone on SVR.
Strikingly, in our study, we reported significant differences regarding vitamin D levels with higher frequency of patients with vitamin D level deficiency (<20 ng/ml) among nonresponders in comparison with the SVR group. There are multiple reports that coincide with our results, demonstrating the association between vitamin D status and outcome of antiviral therapy in patients with chronic HCV viral infection. The first study retrospectively analyzed a cohort of 167 patients treated with PEG-IFN plus ribavirin therapy for hepatitis C and detected an association between lower vitamin D serum levels and failure to achieve SVR .
The second study showed that the addition of vitamin D to PEG-IFN plus ribavirin therapy in treatment-naive patients who were infected with HCV genotype 1 significantly increased the rates of rapid virological response, early virological response (EVR), and SVRs .
The exact mechanism of action leading to improved rapid virological response, EVR, and SVR in patients receiving vitamin D is unknown. However, 1,25-vitamin D3 appears to modulate immunity principally through regulation of T-cell function. The VDR is expressed on virtually every type of cell involved in immunity .
The third study showed that vitamin D supplementation improved the response to antiviral treatment for recurrent HCV in liver transplant recipients .
The fourth study reported higher early virological response rates in CHC treated with SOC plus vitamin D compared with those treated with SOC only .
Our result coincides with Kitson et al. , who reported that vitamin D status is independently associated with cEVR and with SVR only in univariate analysis. Moreover, Martineau et al.  reported that a number of genetic polymorphisms in the vitamin D pathway have been shown to affect vitamin D signaling, and stratification according to such polymorphisms has already being implemented in randomized-controlled clinical intervention studies. Therefore, we believe that analyzing the impact of functionally relevant genetic polymorphisms in the vitamin D cascade on SVR may provide stronger evidence on an intrinsic role of vitamin D metabolism in the pathogenesis and treatment of CHC than analyzing exclusively vitamin D serum levels, which are affected by various parameters including season, sunlight exposure, nutrition, and the metabolic syndrome ,.
Our study revealed that there was a significant difference in allele and genotype frequencies of the VDR polymorphism (Apa1) between patients and controls. This resulted in disagreement with reports in the literature on VDR polymorphisms in patients with chronic liver disease .
Our study reported that there was no significant difference in allele and genotype frequencies of the VDR polymorphism (Fok1) between patients and controls. These data are in disagreement with Vogel et al.  who found a significant difference in allele and genotype frequencies of the VDR polymorphism (Fok1) between patients and controls with chronic autoimmune hepatitis, whereas the opposite results were observed by Fan et al. .
We categorized our patients according to VDR (Fok1) genotype polymorphism as noncarriers/carriers of the C-allele. Our study reported that there was a significant difference regarding C-allele carrier, with higher frequency of the C-allele (mutant type) among nonresponders (92.5%) in comparison with the SVR and control groups (42.5 and 65%, respectively). Interestingly, T-allele frequency (67.5%) (wild type) was more frequent than the C-allele (32.5%) in the SVR group. This coincides with the study of García Martín et al. , who revealed that a common nonsynonymous single nucleotide polymorphism in the VDR gene (rs2228570 T/C) is a predictor of the clinical outcome of combined interferon plus ribavirin therapy. This polymorphism causes a threonine–metionine change in the VDR and, in the multivariate analysis that included the most potent predictors of viral response to combined therapy at baseline, those patients carrying the T-allele in homo- or heterozygosis obtained SVR at a higher rate than patients with the rs2228570 CC genotype. This result is in disagreement with Lange et al. , who reported that the VDR (Fok1) genotype polymorphism was not significantly associated with SVR in response to interferon plus ribavirin therapy in chronic HCV monoinfected patients.
Bioactive vitamin D is an important immune modulator, as, for example, T cells and macrophages crucially depend on calcitriol in various conditions ,. Thus, one may speculate that the 'poor-response' VDR (Fok1) genotype CC may result in lower local concentrations of calcitriol in the HCV-infected liver, resulting in reduced responsiveness to IFN-α or impaired adaptive immune responses .
We categorized our patients according to VDR (Apal) genotype polymorphism as noncarriers/carriers of the rs7975232C allele. Our study revealed a significant difference regarding C-allele carriers with higher frequency of C-allele among nonresponders (92.5%) in comparison with SVR and control groups (65 and 85%, respectively). This coincides with García Martín et al. , who reported a significant association between failure of the combined therapy and haplotype bAt.
Our study demonstrated that, in IL28B polymorphism, T-allele carriers were highly frequent among nonresponders (87.5%) in comparison with SVR (42.5%). Absence of the C-allele (TT genotype) was significantly correlated with failure of response in comparison with CT and CC. The failure of response rates were 52.5, 35, and 12.5% for genotype TT, CT, and CC, respectively. This is in agreement with previous studies reported on genotype 1  and studies conducted on genotype 4 . This result coincides with Thompson et al. , who reported that the key marker for improved treatment response was the CC IL28B type, and the rate of SVR was doubled in patients with the CC compared with the non-CC IL28B type in all populations.
| Conclusion|| |
Pretreatment vitamin D level is significantly higher in responders and can be used as a predictor of response to combination therapy for HCV. VDR gene polymorphisms (Fok1 and Apa1), IL28B polymorphism, pretreatment lower viral load, and lower AFP are independently related to response to PEG-IFN with RBV therapy in CHC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gorodin S, Unal S, Wang Y, Mikhail I, Ludmila B, Tamar C. New tools in HCV diagnosis, in light of the enhanced awareness and the new drugs for treatment. Scientific World J 2013; 2013
Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology 2008; 47
Hendy OM, Abd El Moneam E, Al Shafie M, Sahawy Michaels EL, Rady M, EL Baz S, et al
. Role of IL28B gene polymorphisms in response to the standard of care treatment in Egyptian patients with chronic HCV genotype four. Life Sci J 2011; 8
Asselah T, Estrabaud E, Bieche I, Lapalus M, DE Muynck S, Vidaud M, et al
. Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin. Liver Int 2010; 30
Lange CM, Bojunga J, Ramos-Lopez E. Vitamin D deficiency and a CYP27B1–1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011; 54
Bitetto D, Cussigh A, Fornasiere E. Recipient vitamin D receptor BsmI–TaqI G–T/G–T diplotype predicts acute cellular rejection in liver transplanted patients. Hepatology 2011; 54:S638A.
Zhao YG, Shi BY, Xiao L, Qian YY, Feing K, He XY, et al
. Association of vitamin D receptor FokI and ApaI polymorphisms with human cytomegalovirus disease in the first three months following kidney transplantation. Chin Med J 2012; 125
Zhao YG, Shi BY, Xiao L, Qian YY, Feng K, He XY, et al.
Association of vitamin D receptor FokI and ApaI polymorphisms with human cytomegalovirus disease in the first three months following kidney transplantation. Chin Med J 2012; 125
Jeong SH, Jung YK, Yang JW, Park SJ, Kim JW, Kwon OS, et al
. Effi cacy of peginterferon and ribavirin is associated with the IL28B gene in Korean patients with chronic hepatitis C. Clin Mol Hepatol 2012; 18
Shiffman ML, Suter F, Bacon BR, Nelson DR, Harley H, Sola R, et al
. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N
Engl J Med 2007; 357
Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J. Is an 'a la carte combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group Hepatology 2000; 31
Kau A, Vermehren J, Sarrazin C. Treatment predictors of sustained virologic response in hepatitis B and C. J Hepatol 2008; 49:634–651.
Fried M, Shiffman M, Reddy K, Smith C, Marinos G, Goncales F, et al
. Peginterferon alfa-2a plus Ribavirin for chronic hepatitis C virus infection. N
Engl J Med 2002; 347
Esmat G, Abouzied A, El-Koofy N, EL Raziky M, Mohsen N, Mansour S, et al.
Prevalence and risk factors of asymptomatic hepatitis C virus infection in Egyptian children. World J Gastroenterol 2007; 13
Fung J, Lai C-L, Hung I, Young J, Cheng C, Wong D, et al
. Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and ribavirin. J Infect Dis 2008; 198
Al-Faleh FZ, Aljumah A, Rezeig M, Al-Kanawi M, Al-ahdal M, Al-Humayed S, et al
. Treatment of chronic hepatitis C genotype 4 with interferon and ribavirin combination in Saudi Arabia: a multicenter study. J Viral Hep 2000; 7
Hassan F, Asker H, Al-Khaldi J, Siddique I, Al-Ajmi M, Owaid S, et al
. Peginterferon alfa-2b plus Ribavirin for the treatment of chronic hepatitis C genotype 4. Am J Gastroenterol 2004; 99
Kamal SM, El Tawil AA, Nakano T, He Q, Rasenack J, Hakam SA, et al.
PEG-IFNα-2b and Ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54
Romero-Gomez M. Hepatitis C and insulin resistance: steatosis, fibrosis and non-response. Rev Esp Enferm Dig 2006; 98
Gao B. Cytokines, STATs and liver disease. Cell Mol Immunol 2005; 2
Asselah T, De Muynck S, Broët P, Masliah-planchon J, Bieche I, Blanuet M, et al
. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol 2012; 56
Males S, Gad R, Esmat G, Abobaker H, Anwar M, El Hoseiny M, et al
. Serum alpha-fetoprotein (AFP) level predicts treatment outcome in chronic hepatitis C. Antivir Ther 2007; 12
Derbala MF, Al Kaabi SR, El Dweik NZ, Pasic F, Butt MT, Yakoob R,et al
. Treatment of HCV genotype 4 with PEG-IFNα-2a: impact of bilharziasis and fi brosis stage. World J Gastroenterol 2006; 12
Gad RR, Males S, ElMakhzangy H, Shouman S, Hasan A, Attala M, et al.
Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C. Liver Int 2008; 28
El Makhzangy H, Esmat G, Said M, Refai R, Gad RR, Shouman S, et al
. Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol 2009; 81
Petta S, Cammà C, Scazzone C, Tripodo C, Di marco V, Bono A, et al
. Low vitamin D serum level is related to severe fi brosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010; 51
Abu Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves SVR in chronic hepatitis C (genotype 1) in naïve patients treated with peg interferon alpha and ribavirin: a prospective randomized study. Hepatology 2009; 50
Hewison M. Vitamin D and the intracrinology of innate immunity. Mol Cell Endocrinol 2010; 321
Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, et al
. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology 2011 b; 53
Cammà C, Petta S. Insulin resistance in HCV mono-infected and in HIV/HCV co-infected patients: looking to the future. J Hepatol 2009; 50
Kitson MT, Gregory J, Dore GA, Button P, Mccaughan GW, Crawford DH, et al
. Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection. J Hepatol 2013; 58:467–472.
Martineau A, Timms P, Bothamley G, Peter M. High-dose vitamin D (3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomized controlled trial. Lancet 2011; 377
Rosen C. Clinical practice: vitamin D insufficiency. N
Engl J Med 2011; 364
Bouillon R, Auwerx J, Dekeyser L, Fevery J, Lissens W, De-Moor P, et al.
Serum vitamin D metabolites and their binding protein in patients with liver cirrhosis. J Clin Endocrinol Metab 1984; 59
Falleti E, Bitetto D, Fabris C, Cussigh A, Fontanini E, Fornasiere E, et al
. Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis. World J Gastroenterol 2010; 16
Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002; 35
Fan L, Tu X, Zhu Y, Pfeiffer T, Feltens R, Stoecker W, et al
. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 2005; 20
García Martín E, José AG, Maestro M, Suarez A, Vidaurreta M, Martinez C, et al
. Infl uence of vitamin D-related gene polymorphisms (CYP27B and VDR) on response to interferon/ribavirin therapy in chronic hepatitis C. PLoS One 2013; 8
Lange CM, Bibert S, Kutalik Z, Burgisser P, Andreas C, Dufour J, et al.
A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C. PLoS One 2012; 7
Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al
. Toll-like receptor triggering of a AQ12AQ12AQ12AQ12vitamin D-mediated human antimicrobial response. Science 2006; 311:1770–1773.
Von Essen MR, Kongsbak M, Schjerling P, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010; 11
Thompson AJ, Muir AJ, Sulkowski MS, Fellay J, Shianna KV, Urban T, et al
. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010; 139
De Nicola S, Aghemo A, Rumi MG, Galmozzi E, Valenti L, Soffredini R, et al
. Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4. Hepatology 2012; 55:336–342.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]