[Show abstract][Hide abstract]ABSTRACT: We assessed the virological response of dual therapy with DRV/r, plus raltegravir, maraviroc or etravirine, in virological failure patients and in virologically suppressed patients collected in the Italian Antiretroviral Resistance Database (ARCA).
The primary endpoint was the percentage of patients remaining free of virological failure (confirmed >50 copies/mL or any change in the regimen). Subjects had a resistance test and at least one follow-up visit. Observation was censored at last visit under dual therapy and survival analysis and proportional hazard models were used.
Sixty-seven percent of the 221 patients started DRV/r with RAL, 20.4 % with ETV, and 12.2 % with MAR; 31.2 % virological failures were observed. At survival analysis, the overall proportion of failure was 29.2 % at 1 year and 33.8 % at 2 years. The proportion of failure was lower in patients starting with undetectable vs. detectable viral load (13.3 and 25.2 % vs. 37.4 and 38.8 % at 1 and 2 years, respectively, p = 0.001 for both analyses) and in patients treated with DRV 600 BID vs. 800 QD (HR: 0.56, 95 % CI: 0.31-0.99, p < 0.05). By regimen, the adjusted proportional model showed no significant difference among the three regimens. A significant lower risk of failure was associated with higher GSS (HIV-DB HR: 0.53, 95 % CI: 0.32-0.88, p = 0.014; Rega 0.60, 0.40-0.88, p < 0.01; ANRS 0.55, 0.34-0.90, p = 0.017), while a higher risk of failure with detectable HIV-RNA (3.02, 1.70-5.72, p < 0.001).
Among experienced patients, the best candidates for dual-therapy regimens including DRV/r are those with undetectable viral load and higher GSS.
[Show abstract][Hide abstract]ABSTRACT: Background
We assessed the virological response of DRV/r-based dual therapy in drug-experienced patients included in the Italian antiretroviral resistance database (ARCA).
Materials and Methods
Patients included in the study were treated with DRV/r in association with raltegravir (RAL), etravirine (ETV) or maraviroc (MAR) following treatment failure(s) and with a resistance test and at least one follow-up visit available. Observation was censored at last visit under dual therapy and survival analysis and proportional hazard models were used, taking virological failure (confirmed >50 c/mL HIV-RNA) as the end-point.
Of the total 221 patients included, 149 (67.4%) started DRV/r with RAL, 45 (20.4%) with ETV, 27 (12.2%) with MAR. Patients characteristics at the start of dual regimen were as follows: mean number of previous regimens, nine (IQR: 5–13); non-B subtype, 17 (7.7%); median CD4 count, 347 (IQR: 246–544); undetectable viral load, 74 (33.5%). Full DRV/r resistance was detected in one (0.5%, HIV-DB interpretation system), 13 (5.9%, ANRS) and 17 patients (7.7%, Rega). 69 virological failures (31.2%) were observed during follow-up. At survival analysis, the overall proportion of failure was 29.2% at one year and 33.8% at two years. The proportion of failure was lower in patients starting with undetectable versus detectable viral load (13.3% and 25.2% versus 37.4% and 38.8% at one and two years, respectively, p=0.001 for both analyses) and in patients treated with DRV 600 BID versus 800 QD (HR: 0, 56; 95% CI 0.31–0.99; p<0.05). By regimen, patients treated with DRV/r-RAL showed a non-significant lower proportion of failure (27.7% at one year, 32.0% at two years) if compared with DRV/r-MAR (35.9%, 47.1%) and DRV/r-ETV (34.1%, 34.1% at one and two years). In the adjusted proportional model, no significant difference among the three regimens was detected. A significant lower risk of failure was associated with higher overall GSS (HIV-DB HR: 0.53, 95% CI 0.32–0.88, p=0.014; Rega 0.60, 0.40-0.88, p<0.01; ANRS 0.55, 0.34–0.90, p=0.017), while a higher risk of failure was associated with detectable HIV-RNA (3.02, 1.70–5.72, p<0.001).
Among experienced patients, the best candidates to dual-therapy regimens including DRV/r are those with undetectable viral load and higher GSS. The association with RAL is the most commonly used but no clear advantage with respect to ETV or MAR was observed in our dataset, possibly due to the limited sample size.
Full-text · Article · Nov 2014 · Journal of the International AIDS Society
[Show abstract][Hide abstract]ABSTRACT: To evaluate whether the presence of specific polymorphism in the gene promoter of collagen and some matrix metalloproteinases was associated with the risk of developing pelvic organ prolapse.
A case-control study was carried on 233 women: 137 were cases with ≥ stage II pelvic organ prolapse and 96 were matched controls without pelvic pathologies. Allele and genotype frequencies related to polymorphisms at the Sp1 site of type I collagen and some functional polymorphisms in the promoters of metalloproteinases-1, -3 and -9 have been compared between groups. It has been shown that these single-insertions/deletions polymorphisms located in the promoter region of the genes have a functional significance in the regulation of their transcriptional level and local expression. Genotypes were determined by polymerase chain reaction (PCR) amplification and sequence analysis. SPSS 14.0 software was used for data analysis. Probability values of <0.05 were considered statistically significant.
No difference between groups was found in the genotype distribution polymorphisms for COL1A1, metalloproteinases-9 and -3, while the distribution of the polymorphism of metalloproteinases-1 was significantly increased in the cases when compared with controls (p = 0.04).
Our findings suggest that the polymorphism of metalloproteinases-1 might have a role in mediating susceptibility to pelvic organ prolapse.
Full-text · Article · Dec 2011 · Archives of Gynecology
[Show abstract][Hide abstract]ABSTRACT: High resolution melting (HRM) analysis of PCR amplicons was recently introduced as a closed-tube, rapid, and inexpensive method of genotyping. This study evaluated this system as an option for detecting the three most common mutations in the HFE gene (C282Y, H63D, S65C), accounting for the main form of hereditary haemochromatosis.
Ninety samples, previously screened by direct sequencing, and 27 controls were used. The analysis were performed on the Rotor Gene Q, using the commercial HRM mix containing the Eva Green dye (Qiagen). Specific primers allowed the amplification of the regions of interest in the HFE gene. Following amplification, a HRM analysis was conducted to detect DNA variants. The thermal denaturation profiles of the samples were compared with those of the controls.
One hundred percent of heterozygous and homozygous samples were readily identified. Heterozygotes were easily identified because heteroduplexes altered the shape of the melting curves, but significant differences were also present in the melting curves of the homozygous carries compared with those of the wild-type subjects.
HRM analysis is an appealing technology for HFE gene screening. It is a robust technique that can be widely adopted in diagnostic laboratories to facilitate gene mutation screening.
No preview · Article · Jun 2011 · Clinical Chemistry and Laboratory Medicine
[Show abstract][Hide abstract]ABSTRACT: Gilbert's syndrome leads to intermittent nonhemolytic hyperbilirubinemia through a 70% reduction of hepatic bilirubin glucuronidation, associated with the presence of a homozygous insertion (thymine-adenine, TA) in the uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene promoter (UGT1A1*28). From the clinical point of view the Gilbert's syndrome is considered benign, but recent reports have linked it to drug toxicity. UGT1A1*28 homozygous subjects treated with the protease inhibitor atazanavir or the anti-tumor agent irinotecan are at increased risk of developing adverse drug reactions. To aid clinical decisions and to individualize therapy it is, therefore, important to perform a rapid and accurate molecular diagnosis. Several methodological approaches have been developed to genotype the (TA)n repeat region. In this study we have compared three different techniques: high resolution melting (HRM), multicapillary electrophoresis with QIAxcel system, and direct sequencing. All examined DNA samples (n=90) had concordant genotype calls among the three methods. HRM and QIAxcel system streamlined the laboratory workflow by minimizing analysis time and costs, but the direct sequencing remains the gold standard method. Copyright originale
No preview · Article · Feb 2011 · Biochimica clinica
[Show abstract][Hide abstract]ABSTRACT: The very high cardiovascular (CV) mortality and morbidity rates in hemodialysis (HD) patients are greatly related to atherosclerosis. CCN2 (connective tissue growth factor/CTGF) is a profibrotic factor that is secreted by endothelial cells, involved in atherogenesis, promoting fibroblast proliferation and matrix production. CCN2 protein is significantly increased in complicated fibrous plaques and enhances monocyte migration into atherosclerotic lesions. The aim of this study was to investigate a possible association between CCN2 gene polymorphism and CV morbidity and mortality in HD patients.
98 HD patients, followed for 24 months, were genotyped for the common polymorphism on the CCN2 gene (G-945C). HD patient characteristics were: age 64 ± 13 years, males 64%, diabetes 24%, hypertension 62%, smokers 38%, dyslipidemia 28%, all undergoing standard HD three times weekly.
All-cause mortality was not associated with CCN2 polymorphism (G-945C). In contrast, however, the GG genotype was strongly associated with CV mortality: OR 13 (1.49-155), p = 0.0048. Interestingly, the GG genotype was also greatly associated with the serious CV events of stroke and myocardial infarction in surviving HD patients: OR 13.3 (2.5-87.08), p = 0.0001.
We demonstrate for the first time that CCN2 gene polymorphism is a prognostic risk factor for CV morbidity and mortality in HD patients. These data may have important implications for better understanding the link between accelerated atherosclerosis and increased mortality in HD population.
No preview · Article · Nov 2010 · Blood Purification
[Show abstract][Hide abstract]ABSTRACT: Cardiac extracellular matrix structure is largely under the control of the matrix metalloproteinases (MMPs) whose activity maintains a balance between connective tissue synthesis and degradation. MMP gene polymorphisms, by modifying the level of gene expression, may affect atrial structural remodelling and atrial fibrillation recurrence rate. The aim of this study was to evaluate the association between MMP-1 and MMP-3 polymorphisms and arrhythmia recurrence.
We studied 74 persistent atrial fibrillation patients who underwent electrical cardioversion to restore sinus rhythm. In both patient and reference control groups, identification of MMP-1 and MMP-3 gene polymorphisms was performed by means of polymerase chain reaction according to standard techniques.
Distribution of MMP-1 and MMP-3 genotypes and alleles were similar in atrial fibrillation patients and controls. During a 3-week follow-up period, 37 patients showed atrial fibrillation recurrences. Risk for atrial fibrillation recurrence significantly differed among groups (P = 0.0139) according to 5A and 1G allele presence. In particular, atrial fibrillation recurred in 62% of the patients carrying both 5A and 1G alleles (reference group) compared with no recurrence in patients carrying neither of them.
We observed a significant relationship between MMP-1 and MMP-3 polymorphism and atrial fibrillation recurrences in patients with persistent atrial fibrillation. These findings suggest that genetic factors contribute to determine arrhythmic recurrence rate in persistent atrial fibrillation.
No preview · Article · Oct 2010 · Journal of Cardiovascular Medicine
[Show abstract][Hide abstract]ABSTRACT: Vascular calcification and accelerated atherosclerosis are major causes of death in hemodialysis (HD) patients. Epigenetic mechanisms of gene regulation may be crucial determinants of cellular behavior in uremic conditions, determining an increased risk of cardiovascular morbidity and mortality. The common polymorphisms on different gene promoters have been related to increased coronary artery calcification and associated with cardiovascular outcome in HD population. In this review, we reported the gene polymorphisms of different proteins as negative prognostic risk factors for all-cause mortality in HD patients, independent of traditional risk factors. These data may have important implications for better understanding the pathogenesis of the increased mortality in this population.
No preview · Article · Mar 2010 · Blood Purification
[Show abstract][Hide abstract]ABSTRACT: Vascular calcification and accelerated atherosclerosis are major causes of death in haemodialysis (HD) patients. Matrix metalloproteinases (MMPs) are a family of enzymes, involved in the biology of extracellular matrix and in atherogenesis. MMP1 and MMP3 contribute to the enlargement and instability of atherosclerotic plaque, respectively. The common polymorphisms on MMP1 (2G/2G) and MMP3 (6A/6A) gene promoters have been related to increased coronary artery calcification and to carotid artery stenosis. The aim of this study was to evaluate the association of MMP1 and MMP3 polymorphisms with end-stage renal failure (ESRD) and all-cause mortality risk in HD.
Ninety-nine HD patients, followed-up for 36 months, and 133 matched controls were genotyped for the two polymorphisms. HD patients' characteristics were age 64 +/- 13 years, males 64%, diabetic 24%, hypertensive 62%, smokers 38%, dyslipidaemic 28%, all undergoing standard HD thrice weekly.
ESRD was strongly associated with the combination of 2G/2G and 6A/6A homozygosity: OR 2.57 (0.95-7.4), P = 0.037, but not with isolated 2G/2G and 6A/6A homozygosity (P = 0.09 and P = 0.11, respectively). Isolated 2G/2G was associated with all-cause mortality risk independently from age, gender, diabetes, hypertension, smoking, dyslipidaemia, C-reactive protein, albumin, dialysis vintage and history of cardio-vascular disease: HR 2.96 (1.29-6.80), P = 0.01. A trend for the association of mortality and isolated 6A/6A homozygosity was also observed: HR 3.01 (0.88-10.26), P = 0.078. Combination of 2G/2G and 6A/6A homozygosity significantly increased the mortality risk in the same Cox regression model: HR 4.69 (1.72-12.81), P = 0.003.
In this study, we demonstrated for the first time that MMP-1 and MMP-3 gene polymorphisms are negative prognostic risk factors for all-cause mortality in HD patients, independently from traditional risk factors. These data may have important implications for better understanding the pathogenesis of the increased mortality in HD patients.
No preview · Article · Mar 2009 · Nephrology Dialysis Transplantation
[Show abstract][Hide abstract]ABSTRACT: We investigated whether stromelysin, a candidate gene in atherogenesis, plays a role in atherogenesis of systemic lupus erythematosus (SLE), a leading cause of mortality in SLE.
A genetic study using polymorphism located in the promoter region of stromelysin was performed in 55 Italian patients with SLE. Carotid intimal-medial thickness (IMT) was evaluated by B mode ultrasonography.
All patients with an "abnormal" (> or =0.9 mm) IMT carried at least one 6A allele, and the degree of IMT was significantly greater in patients carrying at least one 6A allele (0.63 +/- 0.22 vs 0.43 +/- 0.04 mm, 5A/6A + 6A/6A vs 5A/5A, p = 0.018).
Our data show that polymorphism of stromelysin promoter may be relevant for SLE-related cardiovascular disease.
Full-text · Article · Mar 2008 · Journal of Clinical Immunology
[Show abstract][Hide abstract]ABSTRACT: Atherosclerosis is an inflammatory disease. Chemokines and chemokine receptors are known to be involved in atherogenesis. Common single nucleotide polymorphisms (SNPs) affect transcription in response to inflammatory stimuli. The aim of this study was to evaluate the correlations between MCP-1, RANTES, SDF-1, CCR2, and CCR5 gene polymorphisms with increased risk of internal carotid artery (ICA) stenosis.
Hundred and twelve patients, consecutively recruited for ICA occlusive disease, and 282 controls were genotyped for MCP-1-2518G, RANTES-403A, CCR5Delta32, CCR2 V64I, and SDF-1-801A polymorphisms.
The frequency of the SDF-1A allele was significantly different between cases and controls: 0.32 vs. 0.20, respectively (OR 1.81; 95% CI 1.25-2.60; p=0.007). The frequency of the RANTES-403G allele was significantly higher in patients with stenosis >70% (OR, 2.45; 95% CI 1.12-5.71; p=0.015). No significant differences were observed with the other polymorphisms.
The reported results seem to correlate the polymorphisms of the genes encoding for SDF-1, RANTES with pathogenesis and progression of ICA occlusive disease. Although suggestive, these results need confirmation in prospective cross-sectional studies.
[Show abstract][Hide abstract]ABSTRACT: Vascular calcification (VC) and accelerated atherosclerosis are major causes of cardiovascular (CV) morbidity and mortality in haemodialysis (HD) patients. Inhibitory proteins are associated with reduced VC and may play a key role in preventing CV in chronic kidney disease (CKD) patients. Fetuin-A, also known as alpha(2)-Heremans-Schmid glycoprotein (AHSG), is a circulating plasma protein with inhibitory effects on VC that has been associated with inflammation and CV mortality in HD patients. In the present study, we investigated the associations between serum fetuin-A levels and its gene (AHSG) polymorphisms in an Italian HD population.
Ninety-six patients on stable chronic HD treatment and 57 healthy controls were genotyped for the common polymorphisms on the AHSG (T256S). In addition, serum fetuin-A levels were tested.
In this study, serum fetuin-A levels were lower in HD patients (0.35 +/- 0.11 g/l) compared with healthy controls (0.62 +/- 0.31 g/l, p < 0.05). In both HD patients and the control group, the distribution of the AHSG gene did not show significant association between low serum fetuin-A levels and the Ser/Ser genotype, known to be associated with a higher CV mortality risk in the HD population. Moreover, the distribution of AHSG gene polymorphisms in HD patients and in healthy controls was similar.
In contrast with previous reports, this study suggests that CKD patients on HD treatment have a similar polymorphism distribution of the AHSG gene compared with the normal population and that the reduction in serum fetuin-A levels in Italian HD patients is not associated with an alteration in the distribution of AHSG T256S polymorphisms.
No preview · Article · Sep 2007 · American Journal of Nephrology