The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection

Background

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim

We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods

A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).

Results

IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10^?7; rs2896019, p = 7.56 × 10^?4); clinically significant steatosis (rs12979860, p = 1.82 × 10^?3; rs2896019, p = 1.27 × 10^?4); and steatosis severity (rs12979860, p = 2.05 × 10^?8; rs2896019, p = 2.62 × 10^?6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.

Conclusions

IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.     

Combinations of simple baseline variables accurately predict sustained virological response in patients with recurrent hepatitis C after liver transplantation

Background

The efficacy of antiviral therapy in patients with hepatitis C recurrence after liver transplantation (LT) is far from optimal and a careful selection of candidates with the best chances to achieve sustained virological response (SVR) is relevant. Moreover, investigating the effects of sustained viral clearance on clinical outcomes is particularly significant. We aimed to identify and combine the best baseline predictors of SVR and to assess the clinical outcomes of antiviral therapy after LT.

Methods

We studied 144 hepatitis C virus (HCV)-infected LT recipients who underwent antiviral therapy following transplantation. Baseline predictors of SVR including donor and recipient interleukin IL28B (IL28B) rs12979860 genotype were evaluated, and the long-term effects of antiviral therapy on clinical outcomes were assessed.

Results

The presence of an IL28B CC genotype with either low viral load (VL), young donor age, or cyclosporine A (CsA)-based immunosuppression identified individuals with 69–80 % probabilities of SVR. In contrast, only 20 % of recipients with a CT/TT IL28B genotype and either high VL, old donor age, or non-CsA immunosuppression achieved an SVR (p = 0.004). Regarding clinical outcomes, the 5-year cumulative probability of graft loss was 2 % for the SVR patients and 48 % for non-responders (p < 0.001).

Conclusions

The use of simple combinations of baseline variables including IL28B polymorphisms identifies HCV-infected LT recipients with different probabilities of response to antiviral treatment. SVR is associated with improved clinical outcomes.     

Prevalence and Impact of Hepatic Steatosis on the Response to Antiviral Therapy in Saudi Patients with Genotypes 1 and 4 Chronic Hepatitis C

Background

Hepatic steatosis in hepatitis C virus (HCV)-infected patients has been shown to enhance the progression of liver fibrosis and decrease the response to antiviral therapy.

Aims

We aimed to determine the role of HCV genotype 4 (HCV-G4) in the prevalence of hepatic steatosis, its impact on antiviral therapy, and its associations and predictive factors in comparison to HCV-G1-infected patients.

Methods

Treatment-naïve HCV patients who were started on pegylated interferon a-2b plus ribavirin therapy in two centers in Saudi Arabia were included. The severity of steatosis was assessed using the METAVIR and NAS (non-alcoholic fatty liver disease [NAFLD] activity score) scoring systems. Sustained virological response (SVR) was studied in relation to the degree of steatosis. Associations between steatosis and multiple demographic, laboratory, and virological factors were examined. HCV-G1 and HCV-G4 patients were compared.

Results

A total of 116 patients (HCV-G4 85 [73.3%]; HCV-G1 31 [26.7%]) were included. The mean age was 50.4 ± 10.7 years and 56.9% were males. In terms of steatosis grading using the NAS scoring system, 50% had steatosis grade 0, 26.7% grade 1, 14.7% grade 2, and 8.6% grade 3, while the overall staging of steatosis revealed that 43.1% had mild steatosis, 42.2% moderate, and 14.7% severe. Gamma-glutamyl transpeptidase (GGT), platelet count, body mass index (BMI), cholesterol level, presence of hyperlipidemia, liver histology stage, and grade were significantly correlated with hepatic steatosis in one or more of the statistical analyses. Twenty-two out of 55 patients (40.0%) had an SVR in the mild steatosis group, compared to 52.7% in the moderate group and 7.3% in the severe group (P = 0.03). The HCV genotype did not correlate with steatosis or SVR.

Conclusion

Our study confirms the high prevalence of steatosis in HCV-G4 and HCV-G1 patients, but with no difference in the grade or score of steatosis between the two genotypes. The grade of steatosis correlates with GGT, platelet count, and BMI, while the NAS score of steatosis correlates with response to antiviral therapy.     

CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV

Background

Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1).

Methods

60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response.

Results

Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p =?0.001; CXCL11: p <?0.001; CCL3: p =?0.006; CCL4: p =?0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p =?0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p =?0.039).

Conclusions

IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.

     

Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study

Background

Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients.

Methods

A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction.

Results

Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043).

Conclusions

The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥4.7 log₁₀IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.     

The virological response in Koreans infected with HCV genotype 1 did not differ between groups treated with a full dose or reduced dose (≥80 % full dose) of peginterferon alfa-2a: a prospective randomized multicenter trial

Purpose

A high rate of sustained viral response (SVR) in Koreans with chronic hepatitis C (CHC) is related to a favorable IL28B genotype. We compared two dosing strategies for peginterferon alfa-2a in Koreans with CHC and defined the combined effect of polymorphisms and dosing on the virological response.

Methods

A total of 178 treatment-naïve patients with CHC genotype 1 were prospectively enrolled. All patients were randomly assigned to treatment with one of two peginterferon alfa-2a regimens: 180 μg per week for 48 weeks (full-dose group) or 180 μg per week during the first 12 weeks followed by 135 μg per week for the next 36 weeks (dose-reduction group). Polymorphisms related to IL28B, ITPA, C20orf194 and SLC29A1 were studied.

Results

SVR rates did not differ between the full-dose and dose-reduction groups (56.5 and 51.2 %, respectively, p = 0.474). The frequency of additional reductions of the peginterferon dose because of adverse events was higher in the full-dose group than in the dose-reduction group. SVR rates in patients homozygous for the IL28B major allele were higher than those in patients for the other IL28B alleles. For patients with unfavorable IL28B genotypes, SVR was less likely to be achieved in the dose-reduction group than in the full-dose group.

Conclusions

In Koreans with HCV genotype 1, the virological response to treatment did not differ between a full dose and reduced dose (≥80 % of full dose) of peginterferon alfa-2a. However, in the patients with unfavorable IL28B genotypes, the full-dose treatment of peginterferon alfa-2a may be beneficial.     

Baseline risk factors for relapse in HIV/HCV co-infected patients treated with PEG-IFN/RBV

Purpose

Hepatitis C virus (HCV) viral relapse (VR) after end-of-treatment response (ETR) in human immunodeficiency virus (HIV) co-infected patients is observed in as many as one in three co-infected patients. The aim of the study was to identify baseline risk factors for VR in HIV/HCV co-infected patients treated with pegylated interferon plus ribavirin (PEG-INF/RBV).

Methods

A total of 212 Caucasian HIV-infected patients with chronic hepatitis C naïve for PEG-INF/RBV were followed prospectively. Patients were included in this prospective study if they had completed a full course of therapy with an ETR. We assessed the relationship between VR rate and potential predictors of relapse.

Results

Of the patients followed, 130 (61.3 %) attained ETR and 103 (79.2 %) achieved sustained virological response (SVR). Consequently, 27 (20.8 %) showed VR. Patients who relapsed were more often male (p = 0.036), carried the non-CC rs14158 genotype in the low-density lipoprotein receptor (LDLr) gene (p = 0.039), had higher baseline HCV RNA levels (p = 0.012), body mass index (BMI) ≥25 kg/m² (p = 0.034), significant liver fibrosis (p < 0.001), had been diagnosed with acquired immunodeficiency syndrome (AIDS)-defining criteria in the past (p = 0.001) and bore the HCV genotypes 1/4 (p = 0.046) when compared with SVR patients. The IL28B genotype was not associated with relapse. Multivariate binary logistic regression showed that high baseline HCV RNA, significant liver fibrosis, HCV genotypes 1/4, being overweight and being diagnosed with AIDS-defining criteria in the past were independently associated with relapse.

Conclusions

Our study shows that VR can be accurately predicted in HIV/HCV co-infected patients on the basis of risk factors which can be identified before treatment.     

Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C

Background

We aimed to clarify the association between single nucleotide polymorphism (SNP) located near interleukin 28B and hepatocellular carcinoma (HCC).

Methods

A cohort comprising 792 patients treated with interferon for chronic hepatitis C was investigated. SNPs at rs8099917 and rs12979860 were determined. Cumulative incidence and HCC risk were analyzed by Kaplan–Meier and Cox proportional hazard analyses for a mean follow-up period of 4.9 years. Fibrosis progression rate (FPR) was determined in these patients with a known time of infection (n = 294).

Results

Cumulative HCC incidence was significantly higher in rs8099917 nonTT (minor homozygote or heterozygote) patients than in rs8099917 TT (major homozygote) patients (20.8 vs. 10.5 % over 10 years, logrank test, p = 0.002). This difference was notable in patients infected with genotype 1 and those treated with pegylated interferon and ribavirin. Among nonSVRs, interferon had a limited effect in suppressing alanine aminotransferase (ALT) and/or α-fetoprotein (AFP) levels in nonTT patients. The suppression of these values after interferon therapy was associated with a lower incidence of HCC. FPR were similar in TT and nonTT patients.

Conclusions

rs8099917 nonTT is related to higher HCC development in patients with HCV genotype 1 and those treated with pegylated interferon and ribavirin. Higher HCC incidence observed in nonTT patients partly results from the limited suppression of ALT and/or AFP by interferon in these patients.     

Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus

Background

Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients.

Methods

A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared.

Results

TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r ²?=?0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p?=?0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p?Conclusions Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.     

Using early viral kinetics to predict antiviral outcome in response-guided pegylated interferon plus ribavirin therapy among patients with hepatitis C virus genotype 1

Background

HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear.

Methods

Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis.

Results

The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log₁₀ decrease, 13 % (7/56) with 1–2 log₁₀ decrease, 51 % (44/87) with 2–3 log₁₀ decrease, 64 % (56/87) with 3–4 log₁₀ decrease, 88 % (72/82) with more than 4 log₁₀ decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response.

Conclusions

The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.     

Association of IL28B Polymorphisms With the Response to Peginterferon Plus Ribavirin Combined Therapy in Polish Patients Infected With HCV Genotype 1 and 4

Background

Three single nucleotide polymorphisms (SNPs) near interleukin-28B (IL-28B) gene were shown to be highly associated with treatment response (SVR) in patients with chronic hepatitis C virus (HCV) infection. There is limited data about the role of single and combined IL-28B polymorphisms in HCV-infected Polish population.

Objectives

This study''s aim was to determine predictability of three IL-28B gene polymorphisms and other known prognostic factors on the treatment response in HCV genotype 1 and 4 infected Polish patients. The effect of IL-28B polymorphisms on therapy was also compared with other known prognostic factors.

Patients and Methods

We genotyped IL-28B polymorphisms (rs12979860, rs12980275 and rs8099917) by polymerase chain reaction-based restriction fragment length polymorphism assay in a group of 293 patients from which a selected cohort of 174 treatment-naiev patients underwent treatment.

Results

We showed that rs12979860 CC [odds ratio (OR) = 4.6, P < 0.001], rs12980275 AA (OR = 2.9, P = 0.002) and rs8099917 TT (OR = 2.2, P = 0.016) genotypes were associated with successful treatment compared to the rs12979860 CT-TT, rs12980275 AG-GG and rs8099917 TG-GG, respectively. Patients bearing of IL-28B profile including the three favourable genotypes do not have much chance of a recovery (OR = 3.4, P = 0.002). Except for IL-28B polymorphisms, there was no association of SVR with any other pretreatment clinical data in analyzed group. The correlation of SNPs with other host and viral factors revealed association of favorable genotypes of IL-28B markers with high levels of alanine aminotransferase and baseline HCV viral load.

Conclusions

IL-28B polymorphisms were the strongest pretreatment predictors of response to pegylated interferon and ribavirin in Polish patients chronically infected with HCV genotype 1 and 4. This study confirm the strongest impact of IL-28B rs12979860 on SVR, nevertheless rs12980275 AA seems to be more important than rs8099917 TT in predicting positive treatment response.     

Interferon-associated hepatic steatosis is related to discrepancies in biochemical and virological responses of chronic hepatitis C to IFN-based therapy

Background and aims

A discrepancy in virological and biochemical responses may occur throughout interferon-based therapy for hepatitis C virus (HCV). We aimed to explore the risk, associated factors, potential mechanisms, and impact on the treatment outcome of the discrepancy.

Subjects and methods

Consecutive 496, chronic HCV-infected patients receiving interferon/ribavirin or peginterferon/ribavirin for 24 weeks with a 24-week follow-up period were enrolled. Of 433 patients with pretreatment liver biopsy, 46 received serial liver biopsies at the end of treatment and end of follow-up to explore the corresponding change in liver histopathology. A virological/biochemical discrepancy was defined as persistently elevated alanine aminotransferase levels throughout the treatment period, despite the seronegativity for HCV RNA at least at the end of treatment. The sustained virological response (SVR) was defined as seronegativity for HCV RNA 6 months after the end of treatment.

Results

Virological/biochemical discrepancy was observed in 28.7 % (137/478) patients. The SVR rate was comparable between patients with (75.2 %, 103/137) and without discrepancy (81.2 %, 277/341, p = 0.14). For patients with discrepancy and SVR, 78 (75.7 %) had a subsequent normalization of alanine aminotransferase. Hepatic steatosis, advanced fibrosis, obesity, older age, peginterferon preparation, and low viral load were independently predictive of a virological/biochemical discrepancy. Serial liver histology showed that significant transient aggravation of hepatic steatosis during interferon-based therapy was observed among patients with a virological/biochemical discrepancy (difference 0.64 ± 0.93, p = 0.022), but not among those without it (difference 0.09 ± 0.69, p = 0.447).

Conclusions

A virological/biochemical discrepancy no longer exists after treatment cessation in most patients, and had little impact on the HCV treatment outcome. Treatment-related hepatic steatosis might play an important role in the pathogenesis of the discrepancy.     

Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

Purpose

A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome.

Methods

The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored.

Results

Patients with SVR (n = 58) and with non-SVR (n = 20) differed significantly in pretreatment HCV RNA level (p = 0.002), fibrosis score (p = 0.047), and cumulative RBV dosage (p = 0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p = 0.01 for group 1, p = 0.004 for group 2, and p = 5E?05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258–2306 region were significantly high in SVR compared to non-SVR patients (p = 0.01 for group 1, p = 0.006 for group 2, and p = 0.0006 for combined). Multivariate analyses revealed that core aa 110 (p = 0.02), NS5A aa 2258–2306 (p = 0.03), and cumulative RBV dosage (p = 0.02) were identified as independent variables associated with the final outcome.

Conclusions

The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.     

The safety and efficacy of peginterferon plus ribavirin in hepatitis C patients concomitant with malignancy other than hepatocellular carcinoma: a multicenter study

Purpose

Cancer patients were generally excluded from the therapeutic guidelines of antiviral therapy. We aimed to evaluate the efficacy and safety of antiviral therapy in patients with hepatitis C virus (HCV) infection concomitant with malignancy other than hepatocellular carcinoma (HCC).

Methods

Twenty-five HCV patients with curative malignancy other than HCC (group A) and 75 sex- and age-matched controls (group B) were recruited into a prospective and case–control analysis. All patients received peginterferon-alpha-2a (PegIFN-alpha-2a) and weight-based ribavirin according to the current treatment recommendations. The primary outcome measurement was sustained virological response (SVR). The safety issue between groups was also compared.

Results

There were 22 (88.0 %) patients of group A and 59 (78.7 %) patients of group B who achieved an SVR (p = 0.39). The SVR rate was comparable between groups both in genotype-1 (HCV-1) (81.8 vs. 72.7 %, p = 0.70) and in genotype-2 (HCV-2) (92.9 vs. 83.3 %, p = 0.66) patients. Multivariate logistic regression analysis demonstrated that the achievement of a RVR (viral clearance during first 4 weeks of treatment) was the strongest predictor of an SVR (odds ratio/95 % confidence intervals [OR/CI]: 6.357/1.50 ? 26.99, p = 0.01), followed by lower baseline viral loads (OR/CI: 0.403/0.174 ? 0.936, p = 0.034) and higher dose of ribavirin exposure (OR/CI: 1.287/1.092 ? 1.517, p = 0.003), whilst previous occurrence of cancer was not associated with SVR. Treatment adherence (76.0 vs. 72.0 %, p = 0.70) and the incidences of grade 3 or more adverse events (28.0 vs. 20.0 %, p = 0.40) were comparable between two groups.

Conclusions

Chronic hepatitis C patients with non-HCC malignancies receiving peginterferon/ribavirin combination therapy carried favorable efficacy and safety outcomes.     

Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene

Background

Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity.

Methods

The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform.

Results

The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09–2.05, p = 0.012; and OR 1.51, 95 % CI 1.09–2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10–2.17, p = 0.013; and OR 1.56, 95 % CI 1.10–2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01–2.21, p = 0.044; and OR 1.52, 95 % CI 1.03–2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28–5.43, p = 0.009; and OR 4.35, 95 % CI 1.93–9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41–12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08–2.85, p = 0.04).

Conclusion

This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD.     

Extended treatment with pegylated interferon alfa/ribavirin in patients with genotype 2/3 chronic hepatitis C who do not achieve a rapid virological response: final analysis of the randomised N-CORE trial

Background and aims

The combination of pegylated interferon alfa/ribavirin will likely remain the treatment of choice for HCV genotype 2/3 patients in financially constrained countries for the foreseeable future. Patients with poor on-treatment response may benefit from treatment extension. This study examined the effect of 48 versus 24 weeks of peginterferon alfa-2a/ribavirin on the sustained virological response (SVR) in patients with HCV genotype 2/3 who did not achieve rapid virological response (RVR).

Methods

N-CORE was a multicentre, randomised, phase III study. HCV genotype 2/3 patients receiving peginterferon alfa-2a/ribavirin without a rapid but with an early virological response were randomised at week 24 to stop treatment (Arm A) or continue to 48 weeks (Arm B). The primary efficacy endpoint was SVR.

Results

Two hundred thirty-five patients were enrolled. End of treatment response was similar in both treatment arms. SVR24 rates were not significantly greater in the extended treatment arm compared with the standard 24-week treatment in either the intention-to-treat or the per-protocol populations (61 vs. 52 %, p = 0.1934 and 63 vs. 52 %, p = 0.1461, respectively). Serious adverse events occurred more frequently in patients receiving extended treatment duration (12 %) versus 24-week therapy (4 %).

Conclusions

It is unclear whether the extension of peginterferon alfa-2a/ribavirin treatment may benefit HCV genotype 2/3 patients who do not achieve RVR. The study was stopped early because recruitment was slower than anticipated, and this may have limited the statistical impact of these findings.     

Interferon regulatory factor 5 polymorphisms in sarcoidosis

Objective

Interferon regulatory factor 5 (IRF5) gene polymorphisms are associated with susceptibility to autoimmune diseases. The aim of this study is to determine the roles of IRF5 single-nucleotide polymorphisms (SNPs) in sarcoidosis.

Methods

A total of 175 Japanese patients with biopsy-proven sarcoidosis and 150 sex-matched controls were genotyped for four IRF5 SNPs: rs729302A/C, rs2004640G/T, rs10954213A/G, and rs2280714G/A. The associations of these SNPs with susceptibility to sarcoidosis were examined.

Results

Carriage of rs10954213A and rs2280714A conferred significant risks for sarcoidosis [carriage of rs10954213A: odds ratio (OR) = 1.96, 95 % confidence interval (CI) = 1.15–3.33, P = 0.01, corrected P = 0.04; carriage of rs2280714A: OR = 1.97, 95 % CI = 1.22–3.16, P = 0.005, corrected P = 0.02]. The haplotype carrying rs10954213A and rs2280714A (haplotype 2) was significantly associated with susceptibility to sarcoidosis (OR = 2.00, 95 % CI = 1.24–3.24, P = 0.004, corrected P = 0.01). rs729302 and rs2004640 were not associated with susceptibility to sarcoidosis, whereas carriage of rs2004640G was protective against pulmonary hypertension (OR = 0.017, 95 % CI = 0.002–0.15, P < 0.001, corrected P < 0.001).

Conclusion

A haplotype carrying two functional SNPs of IRF5, rs10954213A and rs2280714A, was associated with the risk of sarcoidosis in the Japanese population.     

Association between genetic variants in pre-miRNA and colorectal cancer risk in a Chinese population

Introduction

Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA expression levels or processing and then contribute to the susceptibility of cancer development. We hypothesized that SNPs in pre-miRNAs may be associated with the risk of colorectal cancer (CRC).

Materials and methods

We genotyped four common polymorphisms (i.e., rs11614913, rs3746444, rs2910164, and rs2292832) in pre-miRNAs of 353 CRC patients and 540 healthy controls to investigate the association between the SNPs and the risk of CRC using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay.

Results

The rs11614913 CT, TT genotypes, and T allele were associated with an increased risk of CRC compared with the CC genotype and C allele (CT vs. CC: OR = 7.34, 95 % CI 3.76–14.34; TT vs. CC: OR = 13.66, 95 % CI 6.76–27.6; T vs. C: OR = 1.99, 95 % CI 1.63–2.42, respectively). Interestingly, using the rs2910164 GG genotype as a reference, the rs2910164 GC genotype was associated with an increased risk of CRC (OR = 1.49, 95 % CI 1.02–2.18), whereas the rs2910164 CC genotype was associated with a decreased risk of CRC (OR = 0.58, 95 % CI 0.37–0.93). When compared with the rs2910164G allele, rs2910164 C allele was associated with a reduced risk of CRC (OR = 0.80, 95 % CI 0.66–0.97, p = 0.02).

Conclusion

These findings suggest that rs11614913 and rs2910164 polymorphisms may be associated with the etiology of CRC.     

Genetic variants of immune-related genes <Emphasis Type="Italic">IL17F</Emphasis> and <Emphasis Type="Italic">IL10</Emphasis> are associated with functional dyspepsia: A case–control study

Background

Low-grade inflammation may play an important role in pathogenesis of functional dyspepsia (FD). Since cytokines may influence gastric mucosal inflammation, which is associated with FD, we evaluated singe nucleotide polymorphisms (SNPs) of pro-inflammatory IL17F and anti-inflammatory IL10 cytokine genes in patients with FD and healthy subjects (HS).

Methods

Two hundred and thirty-seven consecutive patients with FD (Rome III) and 250 HS were genotyped for IL17F (rs2397084: A/G, rs763780: T/C) and IL10 (rs1800896: G/A, rs1800871: C/T) (PCR-RFLP).

Results

Patients with FD [173 (73%) men, age 38.4±12 years] were comparable with HS [195 (78%) men, age 37.3±12 years] with respect to age and gender. Out of 237 patients, 26 (11%) had epigastric pain, 55 (23.2%) had post-prandial distress syndromes (EPS, PDS), and 156 (65.8%) had EPS–PDS overlap. Among 237 patients with FD, GG (variant) genotype of IL17F (rs2397084) was more common than HS [15 (6.3%) vs. 4 (1.6%), p=0.015, odds ratio (OR)=4.0, 95% confidence interval (CI)=1.3–12.3]. IL17F (rs763780) and IL10 (rs1800896) were comparable among patients and HS (p=0.56, 0.28), respectively. However, TT (variant) genotype of IL10 (rs1800871) was more common among patients than HS [39 (16.5%) vs. 32 (12.8%), p=0.06, OR=1.7, 95% CI=0.98–2.98]. SNPs of IL17F and IL10 (rs2397084, rs763780, rs1800896 and rs1800871) were comparable among patients among sub-types of FD (p=0.80 and 0.44).

Conclusion

SNPs of IL17F (rs2397084) and IL10 (rs1800871) genes are associated with FD.

     

Clinical Outcomes of Hepatitis C Treated with Pegylated Interferon and Ribavirin via Telemedicine Consultation in Northern California

Background

Patients in rural communities are less likely to receive treatment for their hepatitis C (HCV) infection. Telemedicine (TM) consultation can close the gap of access to specialists in remote and under-served areas.

Aim

To determine treatment response and side-effect profiles among HCV patients treated with pegylated interferon and ribavirin via TM consultation in different rural locations in Northern California compared with patients treated in traditional hepatology office visits.

Methods

We performed a retrospective analysis of 80 HCV patients treated at different TM sites (TM, n = 40) and at the University of California Davis Hepatology Clinic (HC, n = 40) between 2006 and 2010, comparing baseline characteristics and clinical outcomes.

Results

At baseline, response to therapy was similar for patients in both groups. Sustained virological response (SVR) was similar in both groups (TM: 55 vs. HC: 43 %; p = 0.36), and a higher proportion of patients treated via telemedicine completed treatment (TM: 78 vs. HC: 53 %; p = 0.03). TM patients had many more visits per week of therapy (TM: 0.61 vs. HC: 0.07; p < 0.001). Neutropenia, GI side effects, fatigue, depression, weight loss, insomnia, and skin rash were similar in both groups. For HC patients incidence of anemia was significantly higher (53 %) than for the TM group (25 %; p = 0.02).

Conclusions

The two groups had equivalent SVR. For the TM group therapy completion was superior and incidence of anemia was lower. This initial study suggests that, as a group, patients with HCV, can be safely and effectively treated via telemedicine.