Mónica García-Álvarez

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)

Soluble markers of inflammation are associated with Framingham scores in HIV-infected patients on suppressive antiretroviral therapy

OBJECTIVE To evaluate the association between biomarkers of inflammation and endothelial dysfunction and Framingham scores (FS) for risk of coronary heart disease (FS-CHD), stroke (FS-Stroke) or any cardiovascular event (FS-CVE) in HIV-infected on suppressive highly active antiretroviral therapy (HAART). METHODS A cross-sectional study was conducted in 73 HIV-infected patients and 23 healthy controls. Inflammatory molecules and endothelial dysfunction markers were measured using a multiplex immunoassay (plasminogen activator inhibitor type 1 (PAI-1), soluble TNF receptor type 1 (sTNF-R1), soluble CD40 ligand (sCD40L), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecules (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1). Outcome variables were FS-CHD ≥10%, FS-Stroke ≥5% and FS-CVE ≥10%. RESULTS Significant differences (p < 0.05) were found comparing controls and HIV patients for PAI-1 (5.4 vs. 13.5 ng/dL), sTNF-R1 (0.85 vs. 1.09 ng/dL), sICAM-1 (529 vs. 858 ng/dL), sE-selectin (73.7 vs. 120 ng/dL), sP-selectin (676 vs. 1511 ng/dL) sCD40L (76 vs. 307 ng/dL), FS-CHD (4% vs. 7.8% L), FS-Stroke (2% vs. 2.8%) and FS-CVE (5% vs. 11%). In HIV-infected patients, the adjusted logistic regression analysis revealed that sTNF-R1 levels were significantly associated with increased FS-CHD>10% (OR: 11.51 (95% CI: 1.14; 115.84); p = 0.038) and FS-CVE (OR: 12.41 (95% CI: 1.25; 123.23); p = 0.031). CONCLUSIONS HIV-infected patients show higher levels of soluble inflammatory and endothelial dysfunction markers than controls and have a two-fold increased FS of presenting coronary heart disease, stroke or cardiovascular events at 10 years. Furthermore, sTNF-R1 displayed the best association with FS of coronary heart disease and any cardiovascular event in our patients.

Mitochondrial haplogroups are associated with clinical pattern of AIDS progression in HIV-infected patients.

Abstract:We performed a cross-sectional study in 469 HIV-infected patients, whose mitochondrial haplogroups were genotyped to study their association with the clinical pattern of AIDS progression. The chance of not having an AIDS progression was 1.45 [95% of confidence interval (CI) = 1.02 to 2.05, P = 0.035) times greater in patients with cluster HV and 1.51 (95% CI = 1.06 to 2.18, P = 0.021) times greater in patients with haplogroup H. However, we only found significant values for haplogroup H (odds ratio = 1.52, 95% CI = 1.01 to 2.32, P = 0.049) in an ordinal logistic regression adjusted by gender, age at HIV infection, intravenous drug users, and hepatitis C virus infection. These data suggest that mitochondrial haplogroups might play a significant role in AIDS progression.

Epidemiologic trends of cancer diagnoses among HIV-infected children in Spain from 1997 to 2008.

Background: The introduction of highly active antiretroviral therapy (HAART) has influenced the incidence of cancer in people with human immunodeficiency virus (HIV) infection. The aim of this study was to evaluate changes in the pattern of cancer rates in HIV-infected children on HAART during over a decade of follow-up. Patients and Methods: We carried out a case-control study. Data were obtained from the records of the minimum basic data set of hospitals in Spain from 1999 to 2008. The epidemiologic trends of cancer diagnoses were evaluated through 3 calendar periods: early-period HAART: 1997–1999, midperiod HAART: 2000–2002, and late-period HAART: 2003–2008). Results: HIV-infected children had higher rates of cancer diagnosis than HIV-negative children (P < 0.001) for both acquired immunodeficiency disease syndrome (AIDS)-defining malignancies (ADM) and non-AIDS-defining malignancies (non-ADM). The highest rates of cancer diagnosis in HIV-positive children were for non-Hodgkin lymphoma, malignant neoplasm of bone and articular cartilage, and Hodgkin lymphoma. When we compared the 3 calendar periods, we found that the rate of ADM diagnoses decreased (from 9.1 to 3.6 to 1.0 cancers per 1000 HIV-children/yr; P < 0.05) and that the rate of non-ADM diagnoses increased (from 0.6 to 5.0 to 8.7 cancers per 1000 HIV-children/yr; P < 0.05). Moreover, the overall rate of cancer diagnoses (ADM plus non-ADM) did not change during the study period (9.7, 8.7, and 9.7 cancers per 1000 HIV-children/yr). Conclusions: HIV-infected children had a dramatic decrease in the rate of ADM diagnoses and an increase in the rate of non-ADM diagnoses. The overall cancer diagnosis rate has not decreased during the past decade and the incidence of cancer still remains high in HIV-infected children in Spain.

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.

High plasma fractalkine (CX3CL1) levels are associated with severe liver disease in HIV/HCV co-infected patients with HCV genotype 1

BACKGROUND Inappropriate persistence of chemokines expression in hepatitis C virus (HCV) infection can drive tissue damage, intrahepatic inflammation, and liver cell injury. The aim of study was to study the association of plasma fractalkine (CX3CL1) levels with fibrosis stage and necroinflammatory activity grade of liver biopsies in human immunodeficiency virus (HIV)/HCV co-infected patients with HCV genotype 1. METHODS We carried out a cross-sectional study on 125 patients. Grading and staging of liver biopsies were carried out by METAVIR score. Plasma CX3CL1 was measured using an immunoassay kit. RESULTS Patients with advanced fibrosis had higher CX3CL1 levels than those with mild or no fibrosis (p=0.010); and patients with severe activity grade had higher CX3CL1 levels than those with low activity grade (p=0.040). Plasma CX3CL1 levels were significantly associated with increased odds of significant fibrosis (odds ratio (OR): 3.47 (95% of confidence interval (95%CI): 1.04; 11.58)), advanced fibrosis (OR: 6.78 (95%CI: 1.70; 26.93)), and moderate necroinflammatory activity grade (OR: 4.09 (95%CI: 1.21; 13.87)). When we analyzed fibrosis stages and activity grades of METAVIR score together, we found a positive significant association of CX3CL1 levels with moderate activity grade/significant fibrosis (OR: 5.49 (95%CI: 1.46; 20.58)) and moderate activity grade/advanced fibrosis (OR: 8.99 (95%CI: 2.06; 39.23)). CONCLUSION Plasma CX3CL1 levels were independently associated with several characteristics of severe liver disease in HIV/HCV coinfected patients with HCV-genotype 1, suggesting a role of CX3CL1 in the pathogenesis of HCV infection.

European mitochondrial DNA haplogroups and metabolic disorders in HIV/HCV-coinfected patients on highly active antiretroviral therapy.

BackgroundMitochondrial DNA (mtDNA) haplogroups play an important role in susceptibility to metabolic disorders and cardiovascular disease. MethodsWe carried out a cross-sectional study in 248 HIV/hepatitis C virus–coinfected patients on highly active antiretroviral therapy to investigate whether mtDNA haplogroups had any influence on metabolic disorders. mtDNA genotyping was performed using the Sequenom MassARRAY platform. Insulin resistance (IR) was estimated using the homeostatic model assessment (HOMA) (HOMA ≥ 3.8), which was calculated as fasting plasma glucose (mmol/L) times fasting serum insulin (mU/L) divided by 22.5. A high atherogenic risk was assessed when the atherogenic index (AI) was ≥3.5. AI was calculated as total cholesterol (mg/dL) divided by HDL (mg/dL). ResultsThe major haplogroup HV and haplogroup H had reduced odds ratios of IR (HOMA ≥ 3.8) [0.45 (95% CI: 0.24 to 0.85) and 0.36 (95% CI: 0.18 to 0.69), respectively], and high AI (AI ≥ 3.5) [0.44 (95% CI: 0.22 to 0.87) and 0.40 (95% CI: 0.19 to 0.80), respectively]. The major haplogroup U had increased odds of IR [2.66 (95% CI: 1.39 to 5.8)]. The major haplogroup JT and haplogroup T had increased odds of high AI [2.86 (95% CI: 1.29 to 6.33) and 4.01 (95%CI: 1.59 to 10.03), respectively]. Additionally, we found that patients belonging to the major haplogroup HV had lower values of serum hepatic growth factor and nerve growth factor, and higher values of adiponectin than patients belonging to the major haplogroup JT (P < 0.05). ConclusionsmtDNA haplogroups were associated with IR and atherogenic dyslipidemia; suggesting that mitochondrial genomics may play a significant role in metabolic disorders and cardiovascular diseases in HIV/hepatitis C virus–coinfected patients on highly active antiretroviral therapy.

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.

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

Abstract: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 < 0.05). The chance of having a fibrosis stage or activity grade increased was 1.20 [95% confidence interval (CI) = 1.0 to 1.44, P = 0.045] and 1.22 (95% CI = 1.1 to 1.45, P = 0.029) times greater for every 100 copies per microliter of plasma bactDNA. Likewise, the odds of having values of FPR > 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.