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Influence of Vitamin D Receptor Gene Polymorphisms on Response to Pegylated Interferon in Chronic Hepatitis B Egyptian Patients.

ABSTRACT: Background:We explored the effect of vitamin D receptor gene (VDR) polymorphisms in response to PEG-IFN treatment in Egyptian chronic hepatitis B (CHB) patients. Methods:Two hundred hepatitis B virus (HBV) patients (42.3±10.7 years) on PEG-IFN ?-2a (180 µg /kg for 48 weeks) and one hundred control subjects (37.3 ±12 years) were enrolled in the study. Vitamin D levels and hepatitis B surface antigen (HBsAg) expression were assessed by ELISA. VDR polymorphisms FokI T>C (rs 10735810), BsmI A>G (rs 1544410), ApaI (rs7975253), and TaqI C>T (rs 731236), were genotyped using real-time PCR. Results:Hepatitis B virus patients expressed significantly greater AST (p=< 0.00001) and ALT (P=< 0.00001), and significantly less vitamin D (P=0.01), than control subjects. Patients with Ff or ff alleles of the FokI single-nucleotide polymorphism (SNP), bb alleles of BsmI SNP, or TT alleles of the Taq1 single nucleotide polymorphisms (SNP) showed greater response to PEG-IFN therapy than those with the FF (P=0.02 and P=0.0002), Bb (P=0.023), or Tt/tt alleles (P=0.01 and P=0.004 respectively). Logistic stepwise regression showed that HBV DNA (r: 0.910, P< .00001), FokI SNP polymorphism (r: 0.919, (P=0.037) and bAt haplotype (r: .926, (P=0.043) are independent factors that determine PEG-IFN treatment response in the HBV-infected patients. Conclusion:VDR gene polymorphisms may be used as treatment response predictors in HBV patients receiving PEG-IFN. FokI SNP and bAt haplotype are independent factors that that can be used to determine PEG-IFN treatment responses in HBV-infected patients.

SUBMITTER: Mostafa-Hedeab G

PROVIDER: S-EPMC5941126 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Influence of Vitamin D Receptor Gene Polymorphisms on Response to Pegylated Interferon in Chronic Hepatitis B Egyptian Patients.

Mostafa-Hedeab Gomaa G Sabry Dina D Abdelaziz Ghada Mostafa GM Ewaiss Manal M Adli Nagla N Fathy Wael W

Reports of biochemistry & molecular biology 20180401 2

<h4>Background</h4>We explored the effect of vitamin D receptor gene (<i>VDR</i>) polymorphisms in response to PEG-IFN treatment in Egyptian chronic hepatitis B (CHB) patients.<h4>Methods</h4>Two hundred hepatitis B virus (HBV) patients (42.3±10.7 years) on PEG-IFN α-2a (180 µg /kg for 48 weeks) and one hundred control subjects (37.3 ±12 years) were enrolled in the study. Vitamin D levels and hepatitis B surface antigen (HBsAg) expression were assessed by ELISA. VDR polymorphisms FokI T>C (rs 10 ...[more]

PMID: 29766002

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Project description:Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C > T (rs12979860) SNP and five VDR SNPs, comprising FokI T > C (rs2228570), BsmI C > T (rs1544410), Tru9I G > A (rs757343), ApaI C > A (rs7975232), and TaqI A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12-5.58], p < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04-3.91], p = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31-2.28], p < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10-2.58], p = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07-2.37], p = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p = 0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06-2.51], p = 0.03) and age ?55 years (OR = 2.25; 95% CI [1.54-3.32], p < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the FokI rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.

Project description:AIM:To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-? (IFNL) polymorphisms. METHODS:This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 ?g pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS:A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION:The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.

Project description:BackgroundPatients with chronic hepatitis C (HCV) infection have high prevalence of vitamin D deficiency. Genome-wide association study data has showed that several genetic variants within vitamin D cascade affect vitamin D function. This study aimed to determine whether genetic polymorphisms of genes in the vitamin D pathway are associated with treatment responses to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection.MethodsThe study included 623 Thai patients from 2 university hospitals diagnosed with chronic HCV infection who were treated with a PEG-IFN and ribavirin. Patients were genotyped for functional variants on vitamin D synthetic pathway including GC (rs4588, rs7041, rs22020, rs2282679), CYP2R1 (rs2060793, rs12794714), CYP27B1 (rs10877012), and DHCR7 (rs12785878). Pre-treatment predictors of sustained virologic response (SVR) at 24 weeks following discontinuation of therapy were identified using a logistic regression analysis.ResultsSVR was achieved by 60.5% of patients (52.9% with HCV genotype 1; 66.7% with HCV non-genotype 1). In 44.6% of HCV genotype 1-infected patients, only the variant rs12785878 in the DHCR7 locus was significantly associated with an SVR. HCV genotype 1 patients who had DHCR7 rs12785878 GT/TT had a higher rate of SVR than those with the GG allele (59.7% vs. 43.4%, P = 0.03), but in HCV non-genotype 1-infected patients, the SVR rate did not differ between the two groups (63.3% and 59.1% for GT/TT and GG allele, P = 0.54). By multivariate analysis, liver fibrosis stage 0-1 (OR = 5.00; 95% CI, 2.02-12.37; P < 0.001), and DHCR7 rs12785878 GT/TT allele (OR = 2.69; 95% CI, 1.03-7.05; P = 0.04) were independent pre-treatment predictors of SVR following PEG-IFN-based therapy in HCV genotype 1 patients. Baseline HCV RNA < 400,000 IU/ml (OR = 1.96; 95% CI, 1.13-3.39; P = 0.02) was the only independent predictor of SVR in HCV non-genotype 1 patients. The polymorphisms of GC, CYP2R1 and CYP27B1 were not associated with treatment outcome even in genotype 1 or non-genotype 1 HCV infection.ConclusionThe DHCR7 polymorphism may be a pre-treatment predictive marker for response to PEG-IFN-based therapy in chronic HCV genotype 1 infection.

Project description:To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group?I?included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.

Dataset Information

Influence of Vitamin D Receptor Gene Polymorphisms on Response to Pegylated Interferon in Chronic Hepatitis B Egyptian Patients.

Publications

Influence of Vitamin D Receptor Gene Polymorphisms on Response to Pegylated Interferon in Chronic Hepatitis B Egyptian Patients.

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