María A. Jiménez-Sousa

Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C.

BackgroundSince 2009, several studies have identified single-nucleotide polymorphisms (SNPs) near the gene encoding for interleukin (IL)-28 (IL28B) that are strongly associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Because this large amount of data includes some inconsistencies, we consider assessment of the global estimate for each SNP to be essential.MethodsRelevant studies assessing IL28B polymorphisms associated with sustained virologic response (SVR) and spontaneous clearance (SC) were identified from a literature search of PubMed up to 9 July, 2012. Studies were eligible studies if they included patients infected with HCV or HCV/HIV, or assessed any SNP located within or near the IL28B gene, SVR data available under standard treatment, and/or SC data in patients with acute HCV infection. Pooled odds ratios were estimated by fixed or random effects models when appropriate. Variables such as HCV genotype, ethnicity, and type of co-infection were studied.ResultsOf 282 screened studies, 67 were selected for SVR and 10 for SC. In total, 20,163 patients were studied for SVR and 3,554 for SC. For SVR, we found that all SNPs showed strong associations in patients with HCV genotypes 1 and 4, whereas the pooled ORs were almost three times lower for genotypes 2 and 3 (rs12979860 and rs8099917). Regarding ethnicity, the SNP most associated with SVR was rs12979860 in white patients, whereas in East Asians it seemed to be rs8099917. The most studied SNP (rs12979860) showed similar results for patients co-infected with HCV/HIV, as for those infected with HCV only. Finally, rs12979860 and rs8099917 both appeared to be associated with SC.ConclusionsIL28B polymorphisms influence both the outcome of interferon treatment and the natural clearance of HCV. However we did not identify a universal predictor SNP, as the best genetic markers differed depending on patient ethnicity, genotype, and type of infection. Nevertheless, our results may be useful for more precise treatment decision-making.

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)

Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin

Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1 alpha, IP-10, TNF-alpha, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1 alpha (4.7-fold increase compared to the control group), TNF-alpha (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1 alpha, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR; fold-change in NcEVR): MIP-1 alpha (4.72;1.71), FGF-b (4.54;1.21), IL-17 (107.1;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient; p value): [ FGF-b versus IL-17 (0.90; 0.00), IL-17 versus VEGF (0.88; 0.00), MIP-1 alpha versus IL-17 (0.84;0.00), FGF-b versus MIP-1 alpha (0.96;0.00), FGF-b versus IL-12p70 (0.90; 0.00), VEGF versus IL-12p70 (0.89; 0.00)]. Th17 immunity has been previously associated with autoimmune diseases and asthma, but this is the first work reporting a role for this profile in viral hepatitis. These results provide an opportunity to evaluate the impact of the treatment with Peg-INF-alpha and RBV on the prevention of immune-driven tissue damage in infected patients.

High plasma CXCL10 levels are associated with HCV-genotype 1, and higher insulin resistance, fibrosis, and HIV viral load in HIV/HCV coinfected patients

BACKGROUND CXCL10 may contribute to the host immune response against the hepatitis C virus (HCV), liver disease progression, and response to HCV antiviral therapy. The aim of our study was to analyze the relationship among virological, immunological, and clinical characteristics with plasma CXCL10 levels in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS We carried out a cross-sectional study on 144 patients. CXCL10 and insulin were measured using an immunoassay kit. The degree of insulin resistance was estimated for each patient using the homeostatic model assessment (HOMA) method. Insulin resistance was defined as a HOMA index higher than or equal to 3.8. Aspartate aminotransferase (AST) to platelet ratio (APRI), FIB-4, Forns index, HGM1, and HGM2 were calculated. RESULTS The variables associated with log(10) CXCL10 levels by univariate analysis were age (b=0.013; p=0.023), prior AIDS-defining condition (b=0.127; p=0.045), detectable plasma HIV viral load (b=0.092; p=0.006), log(10) HOMA (b=0.216; p=0.002), HCV-genotype 1 (b=0.114; p=0.071), and liver fibrosis assessed by all non-invasive indexes (log(10) APRI (b=0.296; p=0.001), log(10) FIB-4 (b=0.436; p<0.001), log(10) Forns index (b=0.591; p<0.001), log(10) HGM1 (b=0.351; p=0.021), and log(10) HGM2 (b=0.215; p=0.018)). However, in multivariate analysis, CXCL10 levels were only associated with HOMA, detectable plasma HIV viral load, HCV-genotype 1 and FIB-4 (R-square=0.235; p<0.001). CONCLUSION Plasma CXCL10 levels were influenced by several characteristics of patients related to HIV and HCV infections, insulin resistance, and liver fibrosis, indicating that CXCL10 may play an important role in the pathogenesis of both HCV and HIV infections.

Transcriptomic correlates of organ failure extent in sepsis

OBJECTIVES Sepsis is characterised by the frequent presence of organ failure and marked immunologic alterations. We studied the association between the extent of organ failure and the transcriptomic response of septic patients. METHODS Gene expression profiles in the blood of 74 surgical patients with sepsis were compared with those of 30 surgical patients with no sepsis. Differentially expressed genes were assessed for their correlation with the sequential organ failure (SOFA) score. RESULTS The expression levels of a group of genes participating in the cell cycle (HIST1H1C, CKS2, CCNA2, CDK1, CCNB2, CIT, CCNB1, AURKA, RAD51), neutrophil protease activity (ELANE, ADORA3, MPO, MMP8, CTSG), IL-1R and IL-18R response correlated directly with SOFA and mortality. Genes involved in T cell (LCK, CD3G, CD3D, ZAP70, ICOS, CD3E, CD28, IL2RB, CD8B, CD8A, CD40LG, IL23A, CCL5, SH2D1A, ITK, CD247, TBX21, GATA3, CCR7, LEF1, STAT4) and NK cell immunity (CD244, KLRK1, KLRD1) were inversely associated with SOFA and mortality. CONCLUSIONS The extent of organ failure in sepsis correlates directly with the existence of imbalanced innate and adaptive responses at the transcriptomic level. Quantification of the expression levels of the genes identified here could contribute to the simultaneous assessment of disease severity and immunological alterations in sepsis.

Mortality of patients infected with HIV in the intensive care unit (2005 through 2010): significant role of chronic hepatitis C and severe sepsis

IntroductionThe combination antiretroviral therapy (cART) has led to decreased opportunistic infections and hospital admissions in human immunodeficiency virus (HIV)-infected patients, but the intensive care unit (ICU) admission rate remains constant (or even increased in some instances) during the cART era. Hepatitis C virus (HCV) infection is associated with an increased risk for hospital admission and/or mortality (particularly those related to severe liver disease) compared with the general population. The aim of this study was to assess the mortality among HIV-infected patients in ICU, and to evaluate the impact of HIV/HCV coinfection and severe sepsis on ICU mortality.MethodsWe carried out a retrospective study based on patients admitted to ICU who were recorded in the Minimum Basic Data Set (2005 through 2010) in Spain. HIV-infected patients (All-HIV-group (n = 1,891)) were divided into two groups: HIV-monoinfected patients (HIV group (n = 1,191)) and HIV/HCV-coinfected patients (HIV/HCV group (n = 700)). A control group (HIV(-)/HCV(-)) was also included (n = 7,496).ResultsAll-HIV group had higher frequencies of severe sepsis (57.7% versus 39.4%; P < 0.001) than did the control group. Overall, ICU mortality in patients with severe sepsis was much more frequent than that in patients without severe sepsis (other causes) at days 30 and 90 in HIV-infected patients and the control group (P < 0.001). Moreover, the all-HIV group in the presence or absence of severe sepsis had a higher percentage of death than did the control group at days 7 (P < 0.001), 30 (P < 0.001) and 90 (P < 0.001). Besides, the HIV/HCV group had a higher percentage of death, both in patients with severe sepsis and in patients without severe sepsis compared with the HIV group at days 7 (P < 0.001) and 30 (P < 0.001), whereas no differences were found at day 90. In a bayesian competing-risk model, the HIV/HCV group had a higher mortality risk (adjusted hazard ratio (aHR) = 1.44 (95% CI = 1.30 to 1.59) and aHR = 1.57 (95% CI = 1.38 to 1.78) for patients with and without severe sepsis, respectively).ConclusionsHIV infection was related to a higher frequency of severe sepsis and death among patients admitted to the ICU. Besides, HIV/HCV coinfection contributed to an increased risk of death in both the presence and the absence of severe sepsis.

IL28RA polymorphism is associated with early hepatitis C virus (HCV) treatment failure in human immunodeficiency virus‐/HCV‐coinfected patients

Due to the poor rate of response to hepatitis C virus (HCV) with pegylated interferon and ribavirin treatment in HCV/HIV coinfected patients, key factors for predicting failure would be useful. We performed a retrospective study on 291 patients on HCV treatment, who had early virological response (EVR) data. IL28B and IL28RA polymorphisms were performed using the GoldenGate® assay. Unfavourable genotypes at IL28B (rs12980275 AG/GG and rs8099917 GT/GG) and an unfavourable allele at IL28RA (rs10903035 G) were associated with early treatment failure. However, only the rs12980275 AG/GG genotype and rs10903035 G allele remained independently associated with early failure in the overall population (OR = 4.15 (95% CI = 1.64–10.54) and OR = 2.00 (95% CI = 1.19–3.36), respectively) as well as in GT1/4 patients (OR = 5.07 (95% CI = 1.81–14.22) and OR = 2.03 (95% CI = 1.13–3.66), respectively). Next, a decision tree showed early treatment failure increased from 37.1% to 65.5% when the unfavourable rs12980275 AG/GG and rs10903035 AG/GG genotypes and HCV‐RNA≥ 500.000 IU/mL were taken into account in GT1/4 patients. In contrast, the failure rate decreased from 37.1% to 11.9% when the favourable rs12980275 AA and rs10903035 AA genotypes were detected. The percentage of patients correctly classified was 78.4%, and AUROC was 0.802 ± 0.028. Regarding GT3 patients, the presence of the GCGCA haplotype (all unfavourable alleles) was associated with early treatment failure, while no association was observed for the IL28B polymorphisms. In conclusion, the IL28RA polymorphism was associated with early treatment failure independently of the IL28B SNPs. The combination of IL28B and IL28RA polymorphisms might be a valuable tool for predicting early treatment failure before starting HCV treatment.

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.

Mitochondrial DNA haplogroups are associated with severe sepsis and mortality in patients who underwent major surgery

OBJECTIVE To analyse whether mitochondrial DNA (mtDNA) haplogroups are associated with severe sepsis and mortality after major surgery. METHODS We performed a case-control study on 240 cardiac or abdominal surgery patients developing severe sepsis (Case-group) and 267 cardiac or abdominal surgery patients without severe sepsis and with systemic inflammatory response syndrome (SIRS, Control-group). Furthermore, a longitudinal substudy was performed for analysing the survival in septic patients. Only European white patients within the N macro-cluster were included. RESULTS Case-group underwent cardiac surgery had lower frequencies of cluster HV (p = 0.005) and haplogroup H (p = 0.005) and higher frequencies of cluster JT (p = 0.028) than Control-group; but no significant differences were found for abdominal surgery. Besides, both cluster HV and haplogroup H were associated with decreased odds of severe sepsis (adjusted odds ratio (aOR) = 0.45 (95%CI = 0.25; 0.82); p = 0.009 and aOR = 0.48 (95%CI = 0.26; 0.87); p = 0.015, respectively) among patients underwent cardiac surgery. In Case-group, 45.4% (109/240) patients died with a survival median of 39 (95%CI = 31.4; 46.62) days. When the clusters were examined, 41% (55/134) patients within cluster HV died versus 71.4% (10/14) patients within cluster IWX (p = 0.018). Additionally, patients within cluster IWX had an increased risk of death (adjusted hazard ratio (aHR) = 2.22; (95%CI = 1.14; 4.34); p = 0.019). CONCLUSIONS European mitochondrial haplogroups might be related to the onset of severe sepsis in patients who underwent major cardiac surgery, but not in patients underwent major abdominal surgery. Besides, mtDNA haplogroups could have influence on mortality in septic patients.

NS3 Resistance-Associated Variants (RAVs) in Patients Infected with HCV Genotype 1a in Spain.

Background Resistance-associated variants have been related to treatment failure of hepatitis C virus (HCV) therapy with direct-acting antiviral drugs. The aim of our study was to analyze the prevalence of clinically relevant resistance-associated variants within NS3 in patients infected with HCV genotype 1a (GT1a) in Spain. Methods We performed a cross-sectional study on 2568 patients from 115 hospitals throughout Spain (2014–2015). The viral NS3 protease gene was amplified by nested polymerase chain reaction and sequenced by Sanger sequencing using an ABI PRISM 377 DNA sequencer. Additionally, clade information for genotype 1a was obtained by using the software geno2pheno (http://hcv.geno2pheno.org/). Results In total, 875 out of 2568 samples were from human immunodeficiency virus (HIV)/HCV-coinfected patients. Q80K was the main RAV found in our patients (11.1%) and the rest of the resistance-associated variants had a lower frequency, including S122G (6.23%), T54S (3.47%), V55A (2.61%), and V55I (2.15%), which were among the most frequent after Q80K. Overall, 286 samples had the Q80K polymorphism (11.1%) and 614 (23.9%) were GT1a clade I. HIV/HCV-coinfected patients had a higher frequency of Q80K and GT1a clade I than HCV-monoinfected patients (12.9% vs. 9.6% [p = 0.012] and 28.5% vs. 21.4% [p<0.001], respectively). Both the prevalence of Q80K and GT1a clade I were not uniform throughout the country (p<0.001), which ranged from 7.3%-22.2% and 15.7%-42.5%, respectively. The frequency of the Q80K polymorphism was far higher in patients infected with GT1a clade I than in patients infected with GT1a clade II (41.5% vs. 1.6%; p<0.001). Conclusions The prevalence of most resistance-associated variants in NS3 was low in patients infected with HCV GT1a in Spain, except for Q80K (11.1%), which was also notably higher in HIV/HCV-coinfected patients. The vast majority of Q80K polymorphisms were detected in GT1a clade I.