Abstract
Background
Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine ...estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known.
Methods
Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient’s characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multivariate analyses.
Results
The analysis included 725 patients. At 48 weeks, the combination of two or more IPTCrS (darunavir/cobicistat with rilpivirine and/or dolutegravir) was associated with higher decreases in Cr-eGFR adjusted median difference (±SD) –3.5 ± 1.6 (95% CI –6.6 to –0.3), P = 0.047, and a decrease up to or higher than 15 mL/min/1.73 m2 was more frequent adjusted OR 3.233 (95% CI 1.343–7.782), P = 0.009, with respect to darunavir/cobicistat alone. The Cr-eGFR changes between darunavir/cobicistat and darunavir/cobicistat with rilpivirine and/or dolutegravir showed more significant decreases in patients taking two or more IPTCrS at 12, 24 and 48 weeks. (ClinicalTrials.gov: NCT03042390).
Conclusions
Concomitant use of darunavir/cobicistat plus IPTCrS dolutegravir, rilpivirine, or both produced an additive effect in the expected Cr-eGFR decrease.
Switching from PIs to dolutegravir in virologically suppressed HIV-infected individuals has not been assessed.
The principal aim was to assess the evolution of bone mineral density (BMD) when ...switching from a ritonavir-boosted PI to dolutegravir in HIV-infected patients with osteopenia or osteoporosis. The secondary objective was to assess the antiviral efficacy and safety of the switch therapy.
This randomized, multicentre study assessed changes in BMD, bone turnover markers, and antiviral efficacy and safety in 73 virologically suppressed patients with osteopenia/osteoporosis taking a ritonavir-boosted PI plus abacavir/lamivudine who were randomized to switch from PI to dolutegravir (DOLU group, n = 37) or continue with a PI (PI group, n = 36). Clinical Trials: NCT02577042.
One and three patients from the DOLU and PI groups, respectively, withdrew prematurely (unrelated to treatment). At 48 weeks, 97.3% versus 91.7%, respectively, maintained viral suppression (snapshot analysis, ITT, M = F). No significant differences were seen between the groups in percentage change from baseline to week 48 in femoral ( P = 0.56) and lumbar spine ( P = 0.29) BMD, although lumbar spine BMD improved by 1.43% (-1.36; 2.92) in the DOLU group 0.12% (-2.83; 2.89) in the PI group. Bone marker values did not vary significantly. At week 48, triglycerides were lower ( P < 0.001) and HDL cholesterol higher ( P = 0.027) in the DOLU group.
Dolutegravir + Kivexa ® was safe and well-tolerated in virologically suppressed patients receiving a PI-based regimen. The lipid profile was better, albeit without significant changes in BMD, probably because of the short follow-up.
Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to ...describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.
Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.
Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.
These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.
Background The link between human immunodeficiency virus/highly active antiretroviral therapy (HAART)—associated lipodystrophy syndrome (HALS) and the use of thymidine analogues has been well ...established. However, to our knowledge, no relationship has been proven between intracellular levels of stavudine (d4T) and HALS. Methods We measured peripheral blood mononuclear cell intracellular levels of d4T-triphosphate (TP) in patients who were receiving d4T as part of their antiretroviral regimens. d4T-TP levels were determined by a validated liquid chromatography-tandem mass spectrometry assay method. The diagnosis of HALS was made in accordance with the criteria of a lipodystrophy severity grading scale. The Student t test, Pearson correlations, 1-way analysis of variance with Bonferroni correction, and stepwise logistic regression were used for statistic analyses. Results This was a cross-sectional study. There were 33 patients: 17 with HALS and 16 without HALS. The median concentration of d4T-TP for patients with HALS was 20.60 femtomoles (fmol)/1 × 106 cells (interquartile range IQR, 14.90–26.92 fmol/1 × 106 cells) and for patients without HALS was 13.85 fmol/1 × 106 cells (IQR, 8.65–20.15 fmol/1 × 106 cells) (P = .013). The median d4T-TP intracellular level in patients who had developed an AIDS-defining condition was 22.50 fmol/1 × 106 cells (IQR, 15.80–27.37 fmol/1 × 106 cells) and in those who had not was 14.40 fmol/1 × 106 cells (IQR, 10.80–20.40 fmol/1 × 106 cells) (P = .037). There were no statistically significant differences in d4T-TP intracellular levels with respect to the presence of metabolic syndrome, the clinical form of HALS (pure lipoatrophic vs mixed), the degree of facial lipoatrophy, the presence of hepatitis C virus infection, and the pair of nucleosides in HAART. d4T-TP levels correlated only with cumulative d4T exposure in time and dose. d4T-TP intracellular levels were independently associated with HALS (odds ratio, 1.58; 95% confidence interval, 1.08–2.32; P = .019). Conclusions Intracellular levels of d4T-TP are strongly associated with the development of HALS.
On March 11, 2004, Madrid suffered one of the worst terrorist attacks in the history of Spain, leaving more than 190 dead and 2,000 injured. For years, the psychological consequences of the attacks ...have been studied; however, its long-term effects on symptomatology and especially on well-being remains unknown. This study aims to explore, through a qualitative approach, pathways and obstacles to the well-being of those affected directly or indirectly by the attacks of March 11 in Madrid. Two focus groups were held, one for indirect victims and one for direct victims. Subsequently, a thematic analysis of the materials obtained was carried out. More than 10 years after the attacks, most of the participants reported great difficulty in achieving well-being. Acceptance and victims’ associations seemed to act as key facilitators, while symptoms, political institutions and the media were the main obstacles. Direct and indirect victims presented similar data although aspects such as guilt and family relationships played a different role in their well-being.
Obesity, diabetes mellitus, and cardiovascular risk are real challenges in systemic lupus erythematosus (SLE) clinical practice and research. The evidence of the burden of these health problems in ...SLE patients is determined by the methods used to assess them. Therefore, the aim of this scoping review is to map current approaches in assessing obesity, diabetes mellitus, and cardiovascular risk burden in SLE patients and to identify existing knowledge gaps in this field. This rapid scoping review was conducted according to the Joanna Briggs Institute methodology and identified 274 articles, of which 73 were included. Most studies were conducted at European institutions and patients were recruited from specialist hospital clinics, the majority of whom were women. The burden of obesity and diabetes mellitus for SLE patients was assessed mainly in terms of prevalence, impact on disease activity, and cardiometabolic risk. The burden of cardiovascular risk was assessed using multiple approaches, mainly imaging and laboratory methods, and risk factor-based scores, although there is great heterogeneity and uncertainty between the methods used. This review highlights the importance of improving and standardizing the approach to obesity, diabetes, and cardiovascular risk in SLE patients through a holistic assessment that includes lifestyle, clinical, biological, and social aspects.
Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism ...and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 MCP-1, plasminogen activator inhibitor type 1 PAI-1) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.
Injuries and bone fractures are the most frequent causes of admission at wildlife rescue centers. Wild birds are more susceptible to open fractures due to their anatomical structure, which can lead ...to osteomyelitis and necrosis. Antibiotic therapy in these cases is indispensable, but the increase of antimicrobial-resistant isolates in wildlife has become a significant concern in recent years. In this context, the likelihood of antibiotic failure and death of animals with infectious issues is high. This study aimed to isolate, identify, and assess the antimicrobial resistance pattern of bacteria in wounds and open fractures in wild birds. To this end, injured birds admitted to a wildlife rescue center were sampled, and bacterial isolation and identification were performed. Then, antimicrobial susceptibility testing was assessed according to the disk diffusion method. In total, 36 isolates were obtained from 26 different birds. The genera detected were
spp. (63.8%),
(13.9%),
(11.1%),
(8.3%), and
(2.8%). Among
isolates,
and
were the most frequent species. Antimicrobial resistance was detected in 82.6% of the isolates, among which clindamycin resistance stood out, and 31.6% of resistant isolates were considered multidrug-resistant. Results from this study highlight the escalating scope of antimicrobial resistance in wildlife. This level of resistance poses a dual concern for wildlife: firstly, the risk of therapeutic failure in species of significant environmental value, and, secondly, the circulation of resistant bacteria in ecosystems.
People with HIV (PWH) may be more susceptible to SARS-CoV-2 infection and worse clinical outcomes. We investigated the disparity in SARS-CoV-2 vaccination coverage between PWH and those without HIV ...(PWoH) in Catalonia, Spain, assessing primary and monovalent booster vaccination coverage from December 2021 to July 2022. The vaccines administered were BNT162, ChAdOx1-S, mRNA-127, and Ad26.COV2.S. Using a 1:10 ratio of PWH to PWoH based on sex, age, and socioeconomic deprivation, the analysis included 201,630 individuals (183,300 PWoH and 18,330 PWH). Despite a higher prevalence of comorbidities, PWH exhibited lower rates of complete primary vaccination (78.2% vs. 81.8%,
< 0.001) but surpassed PWoH in booster coverage (68.5% vs. 63.1%,
< 0.001). Notably, complete vaccination rates were lower among PWH with CD4 <200 cells/μL, detectable HIV viremia, and migrants compared to PWoH (
< 0.001, all). However, PWH with CD4 < 200 cells/μL received more boosters (
< 0.001). In multivariable logistic regression analysis of the overall population, a prior SARS-CoV-2 diagnosis, HIV status, migrants, and mild-to-severe socioeconomic deprivation were associated with lower primary vaccination coverage, reflecting barriers to healthcare and vaccine access. However, booster vaccination was higher among PWH. Targeted interventions are needed to improve vaccine coverage and address hesitancy in vulnerable populations.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity ...criteria for a robust biomarker.
IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation.
Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage.
The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE.
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