Daniel Pineda-Tenor

Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: A meta‐analysis

There is growing evidence that vitamin D is related to chronic hepatitis C (CHC) pathogenicity. We analyzed the relationship of vitamin D status with advanced liver fibrosis (ALF) in CHC treatment‐naïve patients and sustained virologic response (SVR) in CHC patients on pegylated interferon alpha plus ribavirin (pegIFNα/ribavirin) therapy. We performed a meta‐analysis of all eligible studies published to date (April, 2014) in PubMed, SCOPUS, LILACS, and the Cochrane Library, assessing plasma/serum vitamin D levels related to ALF and/or SVR. Pooled odds ratios (ORs) were estimated by either fixed or random effects models. Fourteen studies were selected from the literature search, seven for ALF (1,083 patients) and 11 for SVR (2,672 patients). For liver fibrosis, low vitamin D status was related to a diagnosis of ALF, with the cutoffs of 10 ng/mL (OR = 2.37, 95% confidence interval [CI] = 1.20, 4.72) and 30 ng/mL (OR = 2.22, 95% CI = 1.24, 3.97) being significant, and a near‐significance for 20 ng/mL (OR = 1.44, 95% CI = 0.99, 2.12). Regarding SVR, a significant heterogeneity among studies was found (P < 0.001), and we only found a significant association with SVR for a vitamin D cutoff of 20 ng/mL (OR = 0.53, 95% CI = 0.31, 0.91). When meta‐analysis was performed excluding the outliers, significant pooled ORs were found for all patients (10 ng/mL [OR = 0.48, 95% CI = 0.34, 0.67] and 20 ng/mL [OR = 0.58, 95% CI = 0.45, 0.76]) and GT1/4 patients (10 ng/mL [OR = 0.53, 95% CI = 0.34, 0.81] and 20 ng/mL [OR = 0.54, 95% CI = 0.39, 0.74]). Conclusion: Low vitamin D status in CHC patients is associated with a higher likelihood of having ALF and lower odds of achieving SVR following pegIFNα/ribavirin therapy. (Hepatology 2014;60:1541–1550)

CXCL9, CXCL10 and CXCL11 polymorphisms are associated with sustained virologic response in HIV/HCV-coinfected patients

BACKGROUND The CXCL9, CXCL10 and CXCL11 (CXCL9-11) chemokines play a critical role in eradication of hepatitis C virus (HCV), although HCV-specific immunity often fails to eradicate the HCV, allowing the chronicity of hepatitis C. OBJECTIVE To examine the association between CXCL9-11 polymorphisms and the sustained virological response (SVR) following hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin in HIV/HCV-coinfected patients. STUDY DESIGN We performed a retrospective study in 176 naïve patients who started HCV treatment. The CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 polymorphisms were genotyped by GoldenGate(®) assay. Genetic data were analyzed under recessive inheritance model. The SVR was defined as undetectable HCV viremia through 24 weeks after the end of HCV treatment. RESULTS In the intention-to-treat analysis, the SVR rate was higher in HCV genotype 1/4 (GT1/4) patients carrying rs10336 TT (p=0.042), rs3921 GG (p=0.021), and rs4619915 AA (p=0.024) genotypes; and they had higher likelihood of achieving SVR (adjusted odds ratio (aOR)=3.26 (p=0.038), aOR=4.21 (p=0.019), and aOR=4.08 (p=0.022), respectively). For CXCL haplotype analysis (CXCL9/rs10336, CXCL10/rs3921, and CXCL11/rs4619915), the TGA haplotype (favorable alleles) had better odds of achieving SVR than the CCG haplotype (unfavorable alleles) in GT1/4patients (OR=2.69; p=0.003). No significant results were found in GT2/3 patients. Moreover, similar results were obtained in the on-treatment analysis. CONCLUSIONS The presence of homozygous for the minor allele of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 was related to higher likelihoods of achieving the HCV clearance after pegIFNα/ribavirin therapy in HIV infected patients coinfected with HCV GT1/4.

Association of adiponectin (ADIPOQ) rs2241766 polymorphism and dyslipidemia in HIV/HCV-coinfected patients.

The adiponectin (ADIPOQ) rs2241766 polymorphism is related to metabolic abnormalities. The aim of this study was to evaluate the association of the ADIPOQ rs2241766 polymorphism with serum dyslipidemia and insulin resistance (IR) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)‐coinfected patients.

Single nucleotide polymorphisms of CXCL9-11 chemokines are associated with liver fibrosis in HIV/HCV-coinfected patients.

Background:CXCR3A-associated chemokines (CXCL9-11) are implicated in the pathogenesis of hepatitis C virus (HCV) infection. We analyzed the association between CXCL9-11 polymorphisms and significant liver fibrosis in human immunodeficiency virus (HIV)/HCV-coinfected patients. Methods:We performed a cross-sectional study in 220 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using GoldenGate assay. Three outcome variables related to liver fibrosis were studied: (1) F ≥ 2; (2) APRI ≥ 2; and (3) FIB-4 ≥ 3.25. Results:The percentage of patients with significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was significantly higher for CXCL9 rs10336 TT (P = 0.046, P = 0.010, and P = 0.046, respectively), CXCL10 rs3921 GG (P = 0.046, P = 0.011, and P = 0.049, respectively), and CXCL11 rs4619915 AA (P = 0.035, P = 0.014, and P = 0.057, respectively) genotypes. Moreover, the greater likelihood of having significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was found in carriers of CXCL9 rs10336 TT and CXCL10 rs3921 GG [adjusted odds ratio (aOR) > 2 (P < 0.05)]. These trends were significantly more pronounced in patients infected with HCV-genotype 1 (GT1) [aOR > 3 (P < 0.05)]. Moreover, TGA haplotype showed higher odds for having values of APRI ≥ 2 (aOR = 2.4; P = 0.012) when we considered all patients. This elevated risk for significant liver fibrosis was better represented in patients infected with HCV-GT1, where TGA haplotype had increased odds for having values of F ≥ 2 (aOR = 1.9; P = 0.045), APRI ≥ 2 (aOR = 3.2; P = 0.009), and FIB-4 ≥ 3.25 (aOR = 3.3; P = 0.026). Conclusions:The homozygosity for the minor alleles CXCL9 rs10336 (T), CXCL10 rs3921 (G), and CXCL11 rs4619915 (A) is associated with the higher likelihood of significant liver fibrosis in HIV-infected patients coinfected with HCV-GT1.

FTO rs9939609 polymorphism is associated with metabolic disturbances and response to HCV therapy in HIV/HCV-coinfected patients

BackgroundThe Fat Mass and Obesity-Associated Protein (FTO) gene rs9939609 single nucleotide polymorphism (SNP) has been associated with obesity, metabolic syndrome, insulin resistance (IR), and type 2 diabetes mellitus in the general population. The aim of our study was to examine for the first time the association of the rs9939609 polymorphism with metabolic disturbances, liver disease and virologic response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) in human immunodeficiency virus (HIV)/HCV coinfected patients.MethodsWe carried out a cross-sectional study in 261 patients, of whom 178 were subsequently treated with pegIFNα/RBV therapy. FTO rs9939609 and IFNL3 rs12980275 polymorphisms were genotyped by GoldenGate®. The main outcomes were: 1) metabolic disturbances: insulin resistance (homeostatic model assessment (HOMA-IR)) and overweight (body mass index (BMI)); 2) liver disease (Metavir score): significant fibrosis (F ≥2) and steatosis (>10% fatty hepatocytes); and 3) virologic response to HCV treatment: sustained virologic response (SVR).ResultsThe rs9939609 AA genotype was associated with higher values of BMI (adjusted arithmetic mean ratio (aAMR) = 1.08; 95% confidence interval (95%CI) = 1.03 to 1.14; P = 0.002) and HOMA-IR (aAMR = 1.32; 95%CI = 1.03 to 1.69; P = 0.027). Patients with an rs9939609 AA genotype had higher likelihoods of achieving values of BMI ≥27.5 kg/m2 (adjusted odds ratio (aOR) = 3.46; 95%CI =1.17 to 10.21; P = 0.024), HOMA-IR ≥2.5 (aOR = 2.09; 95%CI = 1.02 to 4.32; P = 0.045), significant fibrosis (aOR = 2.34; 95%CI =1.02 to 5.36; P = 0.045) and steatosis (aOR = 3.65; 95%CI = 1.29 to 10.36; P = 0.015). The rs9939609 AT/AA genotype decreased the likelihood of achieving SVR (aOR = 0.58; 95%CI = 0.34 to 0.99; P = 0.044). A decision tree was performed with the genotypes of HCV, IFNL3 and FTO. The incorporation of rs9939609 significantly improves the prediction of SVR (P <0.05). The overall accuracy was 68.2%.ConclusionsPatients carrying the unfavourable AT/AA genotype of rs9939609 polymorphism had higher odds of metabolic disturbances and a lower likelihood of achieving successful virologic response to HCV therapy.

Mx1, OAS1 and OAS2 polymorphisms are associated with the severity of liver disease in HIV/HCV-coinfected patients: A cross-sectional study

The mechanisms involved in the chronic hepatitis C progression are incompletely understood. The aim was to analyze the association between 2′5′oligoadenylate synthetase 1,2 and 3 (OAS1-3) and myxovirus resistance proteins 1 (Mx1) polymorphisms and severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. We performed a cross-sectional study in 219 patients that underwent a liver biopsy. DNA genotyping for Mx1 (rs469390), OAS1 (rs2285934), OAS2 (rs1293762) and OAS3 (rs2010604) was performed by using GoldenGate assay. The outcome variables ion liver biopsy were: (i) significant fibrosis (F ≥ 2); (ii) moderate activity grade (A ≥ 2). Additive model of inheritance for genetic association test was used. The likelihood of having significant fibrosis (F ≥ 2) was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR) = 0.51; p = 0.040]. Besides, the likelihood of having moderate activity grade (A ≥ 2) was higher in patients carrying Mx1 rs464397 C allele (aOR = 1.63; p = 0.028) and Mx1 rs469390 G allele (aOR = 1.97; p = 0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR = 0.64; p = 0.039) and OAS2 rs1293762 A allele (aOR = 0.41; p = 0.009). In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in HIV/HCV-coinfected patients, suggesting a significant role in the progression of hepatic fibrosis.

TLR3 polymorphisms are associated with virologic response to hepatitis C virus (HCV) treatment in HIV/HCV coinfected patients

BACKGROUND Toll-like receptor-3 (TLR3) is a cellular receptor that may recognize double-stranded RNA (dsRNA) from viruses, resulting in production of proinflammatory cytokines and interferons, which are important for the adaptive immune response. OBJECTIVES To analyze the association between Toll-like receptor-3 (TLR3) polymorphisms (rs3775291 and rs13126816) and virologic response to pegylated interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/HCV coinfected patients. STUDY DESIGN We performed a retrospective study in 321 naïve patients treated with pegIFNα/RBV. Genotyping was performed by using the GoldenGate(®) assay with VeraCode(®). The outcome variables were early virologic response (EVR) and sustained virologic response (SVR). RESULTS In a multivariate analysis, rs3775291 A allele decreased the likelihood of achieving EVR (aOR = 0.20; p = 0.018) and SVR (aOR = 0.38; p = 0.024). Regarding rs13126816, the percentage of EVR decreased with each minor A allele (p = 0.034) in HCV-GT2/3 patients, although no significant association was obtained in the multivariate analysis (p = 0.076). Regarding TLR3 haplotypes (comprised of rs3775291 and rs13126816), GT2/3 patients with AA haplotype had decreased odds of achieving EVR (p = 0.030), whereas GG haplotype increased the likelihood (p = 0.018). Regarding SVR, GG haplotype carriers had increased odds of achieving SVR (p = 0.019, p = 0.043 and p = 0.070 for all, GT2/3 and GT1/4 patients, respectively). Besides, GT1/4 patients with GA haplotype had lower odds of achieving SVR (p = 0.039). CONCLUSIONS Our study shows the first evidence that two TLR3 polymorphisms (rs3775291 and rs13126816) seem to be related to the HCV therapy response in HCV/HIV coinfected patients.

IL7RA polymorphisms predict the CD4+ recovery in HIV patients on cART

The IL7RA polymorphisms have recently been associated with CD4+ T‐cell decline in untreated HIV‐infected subjects and CD4+ T‐cell recovery in patients on combination antiretroviral therapy (cART). The aim of this study was to evaluate whether IL7RA polymorphisms are associated with CD4+ T‐cell recovery in HIV‐infected patients on long‐term cART.

IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients.

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), although mechanisms leading to IR in these patients are not completely understood. The aim of this study was to evaluate the association of interleukin 28B (IL28B) and interleukin 28 receptor alpha (IL28RA) polymorphisms with IR among human immunodeficiency virus (HIV)/HCV‐coinfected patients. We carried out a cross‐sectional study on 203 patients. IL28B (rs8099917) and IL28RA (rs10903035) polymorphisms were genotyped by GoldenGate® assay. IR was defined as homeostatic model assessment (HOMA) values ≥3.00. Univariate and multivariate generalized linear models (GLM) were used to compare HOMA values and the percentage of patients with IR according to IL28B and IL28RA genotypes. In total, 32% (n = 65/203) of the patients had IR. IL28B rs8099917 TT was not significantly associated with HOMA values and IR. In contrast, rs10903035 AA was significantly associated with high HOMA values taking into account all patients (P = 0.024), as well as the subgroups of patients with significant fibrosis (P = 0.047) and infected with HCV genotype 3 (P = 0.024). Additionally, rs10903035 AA was significantly associated with IR (HOMA ≥3.00) in all patients (adjusted odds ratio (aOR) = 2.02; P = 0.034), in patients with significant fibrosis (aOR = 2.86; P = 0.039) and HCV genotype 3 patients (aOR = 4.89; P = 0.031). In conclusions, IL28RA polymorphism (rs10903035) seems to be implicated in the glucose homeostasis because AA genotype increases the likelihood of IR, but this association was different depending on hepatic fibrosis and HCV genotype.

SLC30A8 rs13266634 polymorphism is related to a favorable cardiometabolic lipid profile in HIV/hepatitis C virus-coinfected patients.

Objective:To analyze the relationship of SLC30A8 rs13266634 polymorphism with insulin resistance and dyslipidemia in HIV/hepatitis C virus (HCV)-coinfected patients. Design:Cross-sectional study in 260 HIV/HVC-coinfected patients. Methods:SLC30A8 polymorphisms were genotyped by GoldenGate assay. Genetic data were analyzed under the dominant inheritance model (CT/TT versus CC). Cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), LDL-C/HDL-C, atherogenic index, and homeostatic model assessment of insulin resistance (HOMA-IR) values were assayed for each genotype. Results:rs13266634 CT/TT carriers had higher serum values of HDL-C (P = 0.014) and lower values of LDL-C/HDL-C (P = 0.036) and atherogenic index (P = 0.011) than CC carriers. Additionally, rs13266634 CT/TT carriers had lower percentage of HDL 35 mg/dl or less (P = 0.050) and higher percentage of LDL/HDL at least 3 (P = 0.091) and atherogenic index at least 3.5 (P = 0.003) than CC carriers. When adjusted regression analysis was performed, rs13266634 CT/TT genotype was associated with high serum values of HDL-C [arithmetic mean ratio (AMR) = 1.10 (95% confidence interval, CI = 1.03–1.19) P = 0.006], and low values of LDL-C/HDL-C [AMR = 0.88 (95% CI = 0.79–0.99) P = 0.045] and atherogenic index [AMR = 0.89 (95% CI = 0.81–0.98) P = 0.024]. For categorical outcomes, rs13266634 CT/TT carriers had lower significant likelihood of having atherogenic index at least 3.5 [odds ratio = 0.47 (95% CI = 0.26–0.83) P = 0.009], and very close to significance for LDL-C/HDL-C at least 3 [odds ratio = 0.52 (95% CI = 0.27–1.02) P = 0.056], supporting the protective effect of the CT/TT genotypes. No significant relationship was observed between rs13266634 and HOMA-IR values. Conclusion:rs13266634 CT/TT genotype was associated to higher levels of HDL-C and lower values of cardiovascular risk indices (LDL-C/HDL-C and atherogenic index), but there was a lack of association with HOMA-IR values. Thus, rs13266634 polymorphism might play a significant role in lipid metabolism and cardiovascular risk in HIV/HCV-coinfected patients.