Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients

Objective: To study the association of plasma 25-hydroxy vitamin D (25(OH)D) levels in HIV/HCV coinfected patients with severity of liver disease and virological response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV). Methods: A cross-sectional study in 174 HIV/HCV coinfected patients that underwent a liver biopsy previously to start HCV therapy and a retrospective study of 125 of them. Plasma 25(OH)D levels were quantified by enzyme immunoassay. Liver biopsies were evaluated by METAVIR score. A sustained virological response (SVR) was defined as an undetectable serum HCV viral load (<10 IU/mL) up through 24 weeks after the end of HCV treatment. Results: The median of plasma 25(OH)D level was 48 nmol/L (p25th: 32.5; p75th: 56.1) and 27 (15.5%) had 25(OH)D deficiency (<25 nmol/L). The percentage of 25(OH)D deficiency was higher in patients with significant fibrosis (F ≥ 2) (92.6% vs. 57.1%; p = 0.010) and moderate necroinflammatory activity grade (A ≥ 2) (85.2% vs. 60%; p = 0.043). However, adjusted logistic regression analyses showed that 25(OH)D deficiency was only associated with severity of liver disease [F ≥ 2 (OR = 8.47 (95% of confidence interval (CI) = 1.88; 38.3); p = 0.005) and A ≥ 2 (OR = 3.25 (95%CI = 1.06; 10.1); p = 0.040)]. Moreover, any significant relationship was found between 25(OH)D deficiency and SVR after HCV therapy. Conclusion: Plasma 25(OH)D deficiency was associated with liver disease severity in HIV/HCV coinfected patients, but it was not associated with HCV treatment failure.This work has been supported by grants given by Fondo de Investigacion de Sanidad en España (FIS) [Spanish Health Founds for Research] [grant numbers PI08/0738, PI11/00245; PI08/0928, and PI11/01556], Red Española de Investigación en SIDA (RIS) [AIDS Research Network] [grant numbers RD12/0017/0024 and RD12/0017/0004] and “Fundacion para la Investigación y la Prevención del Sida en España” (FIPSE) [grant number 361020/10]. MGF, MGA, MAJS, and DPT are supported by “Instituto de Salud Carlos III” [grant numbers CM09/00031, CD12/00442, CM10/00105, CM12/00043, respectively].S

Genetic polymorphisms located in TGFB1, AGTR1, and VEGFA genes are associated to chronic renal allograft dysfunction

Background: Persistent inflammation and fibrosis have been related to active progression of renal deterioration and reduced survival of kidney transplant. The aim of this study was to determine the impact of single-nucleotide polymorphisms (SNPs) located in regions related to inflammatory and immune processes on the development of chronic renal allograft dysfunction (CRAD). Methods: A retrospective study was carried out on 276 patients who received kidney transplant (KT). SNPs were genotyped via the SNPlex platform. Statistical analysis was performed with SNPstat and regression logistic analyses were adjusted by age and gender of recipients and donors, cold ischemia time and the number of human leukocyte antigen (HLA) mismatches. Results: From 276 patients with KT, 118 were non-CRAD and 158 were CRAD. Three SNPs showed significant associations with CRAD development: rs1800471 in transforming growth factor beta 1 (TGFB1), rs5186 in angiotensin II receptor type 1 (AGTR1), and rs699947 in vascular endothelial growth factor A (VEGFA). GC genotype of rs1800471 was associated with increased odds of CRAD compared to GG genotype (OR=2.65 (95% confidence interval (CI)=1.09; 6.47), p=0.025), as well as AC and AA genotype of rs699947 assuming a dominant model (OR=1.80 (95% CI=1.02; 3.20), p=0.044). Besides, AC and CC genotypes of rs5186 were associated with reduced odds of CRAD assuming a dominant model (OR=0.56 (95% CI=0.33; 0.96), p=0.033). Conclusion: Our findings suggest that three genes related to immunity and inflammation (rs1800471, rs5186 and rs699947) are associated to susceptibility or protection to CRAD, and might have diagnostic utility in predicting the likelihood of developing CRAD.This work was supported by two Grants from Instituto de Salud Carlos III (Ref: PI08/0738 and PI11/00245) and from Junta de Castilla y León (Ref: GRS 234/A/08). MAJs, AFR and MGF are supported by Grants from Instituto de Salud Carlos III, CM10/00105, UIPY-1377/08 and CM09/00031, respectively.S

Prediction of hepatic fibrosis in patients coinfected with HIV and hepatitis C virus based on genetic markers

Objective: To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients. Design: Retrospective follow-up study. Methods: Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F ≥ 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described. Results: Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001). Conclusions: CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients.Supported by Fondo de Investigacion de Sanidad en España (FIS) (Spanish Health Founds for Research) Grants PI08/0738, PI11/00245; PI08/0928, and PI11/01556; Red Española de Investigación en SIDA (RIS) (AIDS Research Network) Grants RD12/0017/0024 and RD12/0017/0004; and “Fundación para la Investigación y la Prevención del Sida en España” (FIPSE) Grant 361020/10. A. F. R., M. G. F., P. G. B., and M. A. J. S. are supported by “Instituto de Salud Carlos III” Grants UIPY-1377/08, CM09/00031, FI12/00036, and CM10/00105, respectively.S

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

UNLABELLED: 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.Supported by grants from Fondo de Investigación de Sanidad en España (FIS) [Spanish Health Founds for Research], grant number PI11/00245 ; and Red Espaola de Investigación en SIDA (RIS) [AIDS Research Network] grant number RD12/0017/0024; D.P.T., M.G.F., M.A.J.S., and M.G.A. are supported by “ Instituto de Salud Carlos III,” grant numbers CM12/00043, RD12/0017/0024, CD13/0001 and CD12/00442, respectively

Bacterial DNA translocation and liver disease severity among HIV-infected patients with chronic hepatitis C

We carried out a cross-sectional study to explore whether bacterial 16S ribosomal DNA (bactDNA) shows association with severity of liver disease among human immunodeficiency virus/hepatitis C virus coinfected patients. Patients with advanced fibrosis (F3/F4), moderate activity grade (A2/A3), and high fibrosis progression rate (FPR > 0.15) had higher values of plasma bactDNA levels than did patients without these markers of liver disease (P 0.15 was 1.18 (95% CI = 0.98 to 1.42, P = 0.089). In addition, patients with high bactDNA levels (≥175 copies per microliter) had the highest odds of having high values of Metavir score and FPR (P < 0.05). Our data show that bacterial translocation is associated with severe liver disease among human immunodeficiency virus-infected patients with chronic hepatitis C.Supported by grants given by “Instituto de Salud Carlos III” (grant numbers PI08/0738, PI11/00245; ISCIII-RETIC RD06/006, and PI08/0928), and “Fundación para la Investigación y la Prevención del Sida en España” (grant numbers 36443/03 and 361020/10). A. Fernández-Rodríguez, M. Guzman-Fulgencio, M. García-Álvarez, and Mª A. Jimenez-sousa are supported by “Instituto de Salud Carlos III” (grant numbers UIPY1377/08, CM09/00031, CM08/00101, and CM10/00105, respectively).S

IL28B polymorphisms are associated with severity of liver disease in human immunodeficiency virus (HIV) patients coinfected with hepatitis C virus

Objective: To evaluate the association of IL28B polymorphisms and severity of liver disease among human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. Methods: We carried out a cross-sectional study on 223 patients. Liver biopsies were evaluated according to Metavir score. IL28B polymorphisms (rs12980275, rs8099917, rs7248668, and rs11881222) were genotyped using GoldenGate(®) assay. Results: IL28B polymorphisms were in strong linkage disequilibrium, especially the couples rs12980275/rs11881222 and rs8099917/rs7248668. For all patients, the rs12980275 A allele increased the odds for significant fibrosis (F ≥ 2) odds ratio (OR) = 1.68; p = 0.018) and more rapid fibrosis progression (FPR ≥ 0.075 fibrosis units/year) (OR = 1.64; p = 0.035), and decreased the odds for liver steatosis (OR = 0.61; p = 0.046). Furthermore, the rs8099917 T allele increased the odds for F ≥ 2 (OR = 1.93; p = 0.020), FPR ≥ 0.075 (OR = 2.08; p = 0.021), and elevated ALT (≥80 IU/l) (OR = 1.78; p = 0.048). For HCV-genotype 1 patients, rs12980275 A and rs8099917 T alleles decreased the odds for liver steatosis (OR = 0.22; p < 0.001 and OR = 0.39; p = 0.048; respectively). For HCV-genotype 3 patients, the rs12980275 A allele increased the odds for F ≥ 2 ((OR = 6.30; p = 0.012), FPR ≥ 0.075 (OR = 6.40; p = 0.025), and elevated ALT (OR = 4.12; p = 0.037); and the rs8099917 T allele also increased the odds for F ≥ 2 (OR = 7.56; p = 0.027), FPR ≥ 0.075 (OR = 50.8; p = 0.012), and elevated ALT (OR = 5.39; p = 0.043). However, we did not find significant trends in patients infected with HCV-genotype 4. Conclusion: The major alleles of IL28B (rs12980275 A, rs11881222 A, rs8099917 T, and rs7248668 G) are associated with increased odds of liver disease severity in HIV patients infected with HCV-genotype 3. In contrast, HCV-genotype 1 patients carrying the major alleles of IL28B polymorphisms had lower odds for liver steatosis.This work has been supported by grants given by the “Instituto de Salud Carlos III” [grant numbers PI08/0738, PI11/00245; ISCIII-RETIC RD06/006, PI08/0928, and PI11/01556], and “Fundación para la Investigación y la Prevención del Sida en España” (FIPSE) [grant numbers 36443/03 and 361020/10]. AFR, MGF, MGA, and MAJS are supported by Instituto de Salud Carlos III [grant numbers UIPY-1377/08, CM09/00031, CM08/00101, and CM10/00105, respectively]S

Association between IL7RA polymorphisms and the successful therapy against HCV in HIV/HCV-coinfected patients

Interleukin-7 (IL-7) is a critical factor in maintaining or inducing effective antiviral CD4+ and CD8+ T-cell responses. The aim of this study was to examine the association of interleukin-7 receptor-α (IL7RA) polymorphisms with a sustained virologic response (SVR) after hepatitis C virus (HCV) therapy with pegylated interferon-alpha plus ribavirin (pegIFNα/ribavirin) in 177 human immunodeficiency virus (HIV)/HCV-coinfected patients. We performed a retrospective study in 177 naïve patients who started HCV treatment. The IL7RA rs6897932, rs987106, and rs3194051 polymorphisms were genotyped by the GoldenGate® assay. An SVR was defined as undetectable HCV viral load through 24 weeks after the end of HCV treatment. The highest SVR rate was found in patients with the rs6897932 CC (p = 0.029) and rs3194051 GG (p = 0.002) genotypes, and HCV genotypes 2/3 (GT2/3) infected patients with the rs987106 AA genotype (p = 0.048). Additionally, carriers of the rs3194051 GG genotype had a higher likelihood of achieving an SVR [adjusted odds ratio (aOR) = 5.32; 95 % confidence interval (CI) = 1.07-26.94; p = 0.040] than patients with the rs3194051 AA/AG genotype, while rs6897932 CC (aOR = 0.63; p = 0.205) and rs987106 AA (aOR = 0.60; p = 0.213) were not significant. Moreover, three major haplotypes were found: 46.6 % for CTA, 32.4 % for CAG, and 20.7 % for TAA haplotypes. Patients infected with GT2/3 and carriers of the CTA haplotype had lower odds of achieving an SVR (aOR = 0.08; p = 0.004) and the CAG haplotype (favorable alleles) had higher odds of achieving an SVR than other haplotypes (aOR = 21.96; p < 0.001). IL7RA polymorphisms seem to play a significant role in the virological response to pegIFNα/ribavirin therapy in HIV/HCV-coinfected patients, in particular among patients infected with HCV GT2/3.This work has been supported by grants given by Fondo de Investigación de Sanidad en España (FIS) (Spanish Health Funds for Research) (grant numbers PI08/0738, PI11/00245, PI08/0928, and PI11/01556) and Fundación para la Investigación y la Prevención del Sida en España (FIPSE) (grant number 361020/10). This work has been (partially) funded by the RD12/0017/0024 and RD12/0017/0004 projects as part of the Plan Nacional R+D+ I and cofinanced by ISCIII Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS; Refs INT10/009 and INT12/154). Moreover, DP-T, MG-F, MAJ-S and MG-A are supported by Instituto de Salud Carlos III (grant numbers CM12/00043, RD12/0017/0024, CD13/00012 and CD12/00442 respectively).S

HLA-E variants are associated with sustained virological response in HIV/hepatitis C virus-coinfected patients on hepatitis C virus therapy

Objectives: To analyze whether human leukocyte antigen (HLA)-E allelic variants are associated with and may predict response to peg-interferon (IFN) alpha and ribavirin treatment in HIV/hepatitis C virus (HCV)-coinfected patients. Design: Retrospective follow-up study. Methods: We studied 321 naive patients who started HCV treatment. HLA-E genotyping was performed by restriction fragment length polymorphism. A sustained virological response (SVR) was defined as undetectable plasma HCV-RNA up through 24 weeks after the end of HCV treatment. Results: The HLA-E*0101 allele increased the odds of achieving SVR for all patients [adjusted odds ratio (aOR) = 2.03 (95% confidence interval, 95% CI = 1.35-3.06); P = 0.001], for HCV genotype (GT) 1/4 patients (aOR = 1.62 (95% CI = 1.03-2.54), P = 0.035), and for GT2/3 patients [aOR = 9.87 (95% CI = 2.47-31.89), P = 0.001]. For decision tree analysis, the SVR rate increased from 0 to 82.6% and then to 92.5% in GT2/3 patients when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 TT genotype, the SVR rate increased from 33.3 to 54.8% and then to 61.8% when the count of HLA-E*0101 alleles increased. In GT1/4 patients with rs8099917 GT/GG genotype, the SVR rate increased from 15.4 to 22% and then to 44% when the count of HLA-E*0101 alleles increased. The overall percentage of patients correctly classified was 73.2% and the area under the receiver operating characteristic curve (AUROC) was 0.803 ± 0.024. Conclusion: The HLA-E*0101 allele was associated with increased odds of HCV clearance and could help to predict SVR among HIV/HCV-coinfected patients on HCV therapy. This would be helpful to avoid treatment in those less likely to respond to pegylated-interferon-alpha and ribavirin treatment.This work has been supported by grants given by Instituto de Salud Carlos III (Ref. PI08/0738, ISCIII-RETIC RD12/0017 and PI11/00245 to S.R.; Ref. ISCIII-RETIC RD06/006, PI08/0928, and PI11/01556 to J.B.; and Ref. PI11/00870 to J.M.B.), Fundación para la Investigación y la Prevención del Sida en España (FIPSE) (Ref. 361020/10 to J.B.) and Fundación para la Investigación y la Educación en SIDA (F-IES).S

Analysis of IL28B alleles with virologic response patterns and plasma cytokine levels in HIV/HCV-coinfected patients

Objectives: To estimate the impact of interleukin 28B (IL28B) polymorphisms (rs12980275, rs8099917, rs7248668, and rs11881222) and their haplotypes on hepatitis C virus (HCV) treatment (peg-interferon-α and ribavirin) success in 324 HIV/HCV-coinfected patients. We also explore the behavior of plasma cytokine levels. Design: Retrospective follow-up study. Methods: Virologic response to HCV treatment was measured by plasma HCV viral load at different endpoints: rapid virologic response (RVR), early virologic response (EVR), end-of-treatment virologic response (ETVR) and sustained virologic response (SVR). IL28B polymorphisms were genotyped using GoldenGate assay. Finally, 13 cytokines were measured at baseline in 57 plasma samples using a multiplex immunoassay kit. Results: IL28B polymorphisms were strongly associated to virologic responses (RVR, EVR, ETVR, and SVR), although only for HCV genotypes 1 and 4 (P < 0.05). Strong linkage disequilibrium was detected for rs12980275/rs11881222 (r = 0.94) and rs8099917/rs7248668 (r = 0.99). IL28B haplotypes showed association but no improvement on treatment outcome prediction. Thus, the genotyping of only one single-nucleotide polymorphism was enough for predicting treatment response in GT1/4 patients with favorable rs12980275 (AA) genotype, while for subjects harboring unfavorable genotypes, the inclusion of rs8099917 was useful (SVR increased from 31 to 45%). Moreover, patients with rs12980275 (AA) that achieved SVR showed reduced plasma levels of Th1 (IFN-γ), Th2 (IL-6 and IL-9), and proinflammatory (TNF-α) cytokines. Conclusion: The presence of IL28B polymorphisms was significantly associated with HCV clearance during and after HCV therapy. The evaluated cytokine profile was much more favorable in patients with rs12980275 (AA) who achieved SVR.This work has been supported by grants given by ‘Instituto de Salud Carlos III’ [grant numbers PI08/0738, PI11/00245; ISCIII-RETIC RD06/006, PI08/0928 to JB; and PI11/00870], ‘Fundación para la Investigación y la Prevención del Sida en España’ (FIPSE) [grant numbers 36443/03 and 361020/10] and ‘Fundación para la Investigación y la Educación en SIDA’ (IES Foundation).S

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.This work has been supported by grants given by Fondo de Investigación de Sanidad en España (FIS) [Spanish Health Funds for Research] [grant numbers PI08/0738, PI11/00245; PI11/00870, PI08/0928, and PI11/01556], Red Española de Investigación en SIDA (RIS) [AIDS Research Network] [grant numbers RD12/0017/0024, RD12/0017/0004 and RD12/0017/0031], “Fundación para la Investigación y la Prevención del Sida en España” (FIPSE) [grant number 361020/10]. MGF, MGA, MAJS, and DPT are supported by “Instituto de Salud Carlos III” [grant numbers RD12/0017/0024, CD12/00442, CD13/00013, and CM12/00043, respectively]. JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS)S