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

The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection

The aim of this study was to compare cytokine expression on both gene and protein levels in acute and chronic phase of HIV type 1 (HIV-1) infection. Thirty four patients were enrolled for cytokine expression analysis on protein level in acute and chronic stage of HIV-1 infection. Using PCR array technology, expression of 84 cytokine genes was measured in 3 patients in acute and 3 patients in chronic stage of HIV-1 infection. Bead-based cytometry was used to quantify levels of Th1/Th2/Th9/Th17/Th22 cytokines. The results showed statistically significant increase of 13 cytokine gene expression (cd40lg, csf2, ifna5, il12b, il1b, il20, lta, osm, spp1, tgfa, tnfsf 11, 14 and 8) and downregulation of the il12a expression in chronic HIV type 1 infection. Concentrations of IL-10, IL-4 and TNF-α were increased in the acute HIV type 1 infection when compared to control group. During chronic HIV type 1 infection there was an increase of IL-10, TNF-α, IL-2, IL-6, IL-13 and IL-22 levels when compared to control group. Comparison of cytokine expression between two stages of infection showed a significant decrease in IL-9 concentration. This study showed changes in cytokine profiles on both gene and protein levels in different stages of HIV-infection

IL7RA

Background: Our aim was to determine whether α-chain of the IL-7 receptor (IL7RA) polymorphisms (rs10491434, rs6897932 and rs987106) are associated with the clinical pattern of AIDS progression in ART-naïve HIV-infected patients. Materials and methods: We carried out a cross-sectional study in 673 HIV-infected patients who were classified into three groups according to the clinical pattern of AIDS progression (188 long-term nonprogressors (LTNPs), 334 moderate progressors (MPs) and 151 rapid progressors (RPs)). Additionally, 134 healthy blood donors participated as a Control-group. We selected three IL7RA polymorphisms located at three regulatory regions [rs6897932 (exon 6), rs987106 (intronic region) and rs10491434 (3'UTR)]. DNA genotyping was performed using Sequenom's MassARRAY platform. Results: The Control-group and all HIV-infected patients had similar age and percentage of males. LTNP-group was older at HIV diagnosis and at the inclusion in the study and had higher percentage of intravenous drug users (IDU) (P 0·05), and among different subgroups of HIV patients according to AIDS progression (LTNPs, MPs and RPs) (P > 0·05). The adjusted logistic regression did not show any significant association between IL7RA polymorphisms and AIDS progression. Conclusions: IL7RA polymorphisms (rs6897932, rs987106 and rs10491434) were not associated with AIDS progression in Spanish population. Therefore, IL7RA polymorphisms do not seem to help us to understand HIV pathogenesis in untreated HIV-infected patients with different clinical evolution.This work has been (partially) funded by the RD12/0017/0037 and RD12/0017/0024 projects as part of the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011 and cofinanced by Instituto de Salud Carlos III (Subdirección General de Evaluación) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT13/0010/0028, Fondo de Investigación Sanitaria (FIS) (grant numbers PI13/02016, PI14/00882, PI14CIII/00011), Comunidad de Madrid (grant numbers S-2010/BMD-2351 and S-2010/BMD-2332), Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo (CYTED) (grant numbers 214RT0482), and the ‘Programa de Investigación de la Consejería de Sanidad de la Comunidad de Madrid’ to JLJ.CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, the Consolider Programand CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. This work was supported partially by a Marie Curie International Research Staff Exchange Scheme Fellow-ship within the 7th European Community Framework Program, project No. PIRSES-GA-2012-316730 NANOGENE and cofinanced by the Polish Ministry of Science and Higher Education (grant No. W21/7PR/2013). LMM, MAJS and AFR are supported by ‘Instituto de Salud Carlos III’ [grant numbers CD14/00002, CD13/00013 and CP14/0010, respectively].S

Chirac\u27s role in French foreign policy during the Iraqi crisis

This study focused on the importance of individuals in foreign-policy decision making process. Specifically how Chirac steered French foreign policy in opposing the US in its bid to war against Iraq. The role of Chirac was analyzed using a Constructivist account of foreign policy. The study was divided into two major chapters Chirac\u27s set of actions in the domestic and international level. It is essential to first analyze the domestic level because foreign policies are created and affected by local factors in a country. Chirac considered public opinion regarding the war and French business interests in France to oppose the Iraqi war. In the international level, Chirac formed alliances with different states, used international organizations as a stage to voice out his opposition, and used the international media to project French foreign policy

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

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

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