HIV-1 integrase strand transfer inhibitors (INSTIs) are a novel class of antiretroviral drugs with a good safety profile. Several INSTIs have been developed clinically.
The purpose of this review is ...to examine the safety data of the three FDA-approved INSTIs: Raltegravir (RAL), Elvitegravir (EVG) and Dolutegravir (DTG). The most relevant papers related to the safety profile of integrase inhibitors were selected and summarized.
INSTIs have demonstrated a favorable safety profile in Phase II and III trials. The most common clinical adverse events reported were diarrhea, nausea and headache. DTG and cobicistat, a component of Stribild(™), increase serum creatinine and decrease estimated creatinine clearance due to inhibition of active tubular secretion of creatinine without affecting renal glomerular function. INSTIs intrinsic potency, together with an outstanding safety profile, preludes an important role for these drugs to build up highly active antiretroviral treatment (HAART) in the near future.
HIV-1-infected patients with lipodystrophy show insulin resistance, dyslipidemia and other signs of metabolic syndrome. Fibroblast growth factor-21 (FGF21) is a novel metabolic regulator that has ...been suggested to exert beneficial effects on metabolic homeostasis and insulin sensitivity. Our goal was to determine the relationship between FGF21 levels and metabolic alterations in these patients.
Serum FGF21 levels were analyzed in 179 individuals belonging to four groups: HIV-1-infected, antiretroviral-treated patients that have developed lipodystrophy (n = 59); HIV-1-infected, antiretroviral-treated patients without lipodystrophy (n = 45); untreated (naive) HIV-1-infected patients (n = 41); and healthy control individuals (n = 34). Serum FGF21 levels were correlated with parameters indicative of altered fat distribution, metabolic and cardiovascular risk, and in relation to HIV-1 infection and antiretroviral treatment regimens.
Serum FGF21 levels were increased in all HIV-1-infected patients, but the increases were most marked in those with lipodystrophy. FGF21 levels showed a strong positive correlation with indicators of lipodystrophy (trunk/apendicular fat ratio, waist-to-hip ratio), insulin resistance (fasting glucose, HOMA-R), dyslipidemia (low-density lipoprotein cholesterol), and liver injury (γ-glutamyltransferase).
FGF21 levels are increased in HIV-1-infected patients, especially in those with lipodystrophy, and this increase is closely associated with insulin resistance, metabolic syndrome and makers of liver damage. Further research will be required to determine whether the increase in FGF21 levels is caused by a compensatory response or resistance to FGF21, and to establish the potential of FGF21 as a biomarker of altered metabolism in HIV-1-infected, antiretroviral-treated patients.
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.
Confirmatory factor analytic studies have shown that posttraumatic stress disorder (PTSD) symptoms included in the fifth edition of the Diagnostic and Statistical Manual Disorders (DSM-5) may be ...better explained by two 6-factor models (the Externalizing Behaviours model and the Anhedonia model) and a 7-factor Hybrid model. The latter model comprises the symptom clusters of intrusion, avoidance, negative affect, anhedonia, externalizing behaviours, and anxious and dysphoric arousal. This model has received empirical support mainly in American samples. Of note, there have been a limited number of studies conducted on samples from other countries.
This study aimed to examine the underlying dimensionality of DSM-5 PTSD symptoms in a Spanish clinical sample exposed to a range of traumatic events.
Participants included 165 adults (78.8% females) seeking treatment in trauma services in the Madrid area (Spain). PTSD was assessed using the Global Assessment of Posttraumatic Stress Scale 5, a Spanish self-report instrument assessing posttraumatic symptoms according to the DSM-5 criteria. Confirmatory factor analyses were conducted in Mplus.
Both the 7-factor Hybrid model and the 6-factor Anhedonia model demonstrated good and equivalent fit to the data.
The findings of this study replicate and extend previous research by providing support for both the 7-factor Hybrid model and the 6-factor Anhedonia model in a clinical sample of Spanish trauma survivors. Given equivalent fit for these two models and the fewer number of latent factors in the Anhedonia model, it was selected as optimal in a traumatized Spanish sample. Implications and future research directions are discussed.
Conflicting reports on the effects of efavirenz (EFV) and lopinavir/ritonavir (LPV/r) on subcutaneous adipose tissue (SAT) have been described.
The aim was to assess the 48-week molecular and ...clinical effects of LPV/r and EFV, combined with tenofovir/emtricitabine (TDF/FTC), on SAT of HIV-infected, antiretroviral-naive patients.
Forty-four adults were started on LPV/r or EFV combined with TDF/FTC. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by dual x-ray absorptiometry scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) and transcripts for mtDNA-encoded proteins and genes involved in inflammation, adipocyte differentiation, and metabolism were assessed in paired SAT biopsies.
Whole-body fat and limb fat mass increased in the LPV/r and EFV groups. MtDNA and cytochrome oxidase subunit II did not change, and cytochrome b increased significantly in EFV-treated patients. Tumor necrosis factor alpha and monocyte chemotactic protein-1 gene expression did not change in the LPV/r group, but these significantly increased in the EFV group. Interleukin 18 decreased in the LPV/r group, whereas it increased in the EFV group.
Starting TDF/FTC plus EFV was associated with an increased expression of genes encoding for inflammatory cytokines in SAT in naive patients. Therapy with TDF/FTC plus LPV/r or EFV was associated with an increase in subcutaneous fat mass.
Sustainability has increasingly become key in universities, as the objectives of sustainable development are essential to establish policies, guidelines and indicators that guide institutions to be ...more sustainable. This recognition has led many authors to develop methods to assess universities based on their performance in terms of sustainable development. This article presents a review of these methods. The review focuses on identifying existing methods and classifying the methods according to seven characteristics: (1) nature of the data, (2) data collection, (3) scope, (4) level of implementation, (5) pillars of sustainability, (6) university function, (7) country perspective taken, which will allow identifying the differences between methods when assessing sustainability. The seven criteria established for the characterization of the sustainability assessment methods contain a total of 27 sub-criteria distributed among the properties. The main contribution of the study is the analysis of the revised methods through a comprehensive characterization and systematic grouping. In the discussion, the results are examined by looking at the comprehensiveness, heterogeneity and objectivity of the methods reviewed. Together with previous research in the area, this study highlights the need to continue deepening the design of sustainability assessment methods with standardized criteria.
In the present study, we investigated the characteristics of memories concerning both traumatic events (war-related memories) and positive life events (happy memories) in a group of Palestinian ...students who were victims of war and military violence. An ad hoc questionnaire was developed to explore differences in how the traumatic and happy events were recalled, both in relation to the actual events experienced and in relation to their phenomenological features in autobiographical memory. Traumatic memories were observed to be richer in sensory characteristics, more vivid, and generally more detailed; the emotions associated with traumatic episodes were more intense and played a key role in recall, as did recurrent thoughts and discussion of events and post-event autobiographical memories. In sum, traumatic memories are more complex than non-traumatic ones given their more sensory and analogical nature, which can also undermine accuracy of recall. The clinical implications of these findings and possible directions for future research are discussed.
To carry out a cost-utility analysis of the application of the Oncotype genomic test to inform the decision to use or not to use chemotherapy in the Basque Country (Spain).
The cost-utility study was ...carried out using a discrete event simulation model representing the natural history of breast cancer. The decision of treatment with chemotherapy based on Oncotype was compared with the standard of treatment based on clinical-pathological criteria. The model included clinical data from Basque hospitals and the literature and was processed by deterministic and probabilistic analysis to calculate the incremental cost-effectiveness ratio (ICER), the cost-effectiveness plane, the acceptability curve and the expected value of perfect information. The study adopted both a health and societal perspective.
From a health perspective, the deterministic analysis estimated an ICER for Oncotype of 17,453 euros/quality-adjusted life year (QALY), discount included, and 9,613 euros/QALY without the discount. Eighty five percent (85%) of the simulations were below the efficiency threshold for Spain. The parametric variability associated with the Oncotype results was the main uncertainty factor in the decision.
Oncotype is a cost-effective intervention from a health system perspective since each QALY gained costs less than 25,000 euros. From a societal perspective, it is dominant since it provides greater health and is accompanied by cost savings.
Llevar a cabo un análisis de coste-utilidad del uso del test genómico Oncotype en el País Vasco (España) para informar la decisión de uso de quimioterapia.
El estudio de coste-utilidad se realizó mediante un modelo de simulación de eventos discretos que representó la evolución natural del cáncer de mama. La decisión de tratamiento con quimioterapia basada en Oncotype se comparó con el estándar de tratamiento basado en criterios clínico-patológicos. El modelo incluyó datos clínicos de hospitales vascos y la literatura para calcular la ratio de coste-efectividad incremental (RCEI) mediante análisis determinista y probabilístico, el plano coste-efectividad, la curva de aceptabilidad y el valor esperado de la información perfecta. El estudio adoptó una perspectiva tanto sanitaria como social.
El análisis determinista estimó una RCEI para Oncotype de 17.453 euros/año de vida ajustado por calidad (AVAC) con descuento y 9613 euros euros/AVAC sin descuento, desde la perspectiva sanitaria. El 85% de las simulaciones estuvieron por debajo el umbral de aceptabilidad para España. La variabilidad paramétrica asociada a los resultados de Oncotype fue el mayor factor de incertidumbre de la decisión.
Oncotype constituye una intervención coste-efectiva, ya que cada AVAC ganado tiene asociado un coste inferior a 25.000 euros. El test es dominante desde una perspectiva social al lograr mayor salud acompañada de ahorros.
Liver resection remains the gold standard for hepatic metastases. The future liver remnant (FLR) and its functional status are two key points to consider before performing major liver resections, ...since patients with less than 25% FLR or a Child-Pugh B or C grade are not eligible for this procedure. Folinic acid (FA) is an essential agent in cell replication processes. Herein, we analyze the effect of FA as an enhancer of liver regeneration after selective portal vein ligation (PVL). Sixty-four male WAG/RijHsd rats were randomly distributed into eight groups: a control group and seven subjected to 50% PVL, by ligation of left portal branch. The treated animals received FA (2.5 m/kg), while the rest were given saline. After 36 h, 3 days or 7 days, liver tissue and blood samples were obtained. FA slightly but significantly increased FLR percentage (FLR%) on the 7th day (91.88 ± 0.61%) compared to control or saline-treated groups (86.72 ± 2.5 vs. 87 ± 3.33%;
< 0.01). The hepatocyte nuclear area was also increased both at 36 h and 7days with FA (61.55 ± 16.09 µm
, and 49.91 ± 15.38 µm
;
< 0.001). Finally, FA also improved liver function. In conclusion, FA has boosted liver regeneration assessed by FLR%, nuclear area size and restoration of liver function after PVL.
Parenteral administration of horse- and sheep-derived antivenoms constitutes the cornerstone in the therapy of envenomations induced by animal bites and stings. Depending on the type of neutralising ...molecule, antivenoms are made of: (i) whole IgG molecules (150 kDa), (ii) F(ab')(2) immunoglobulin fragments (100 kDa) or (iii) Fab immunoglobulin fragments (50 kDa). Because of their variable molecular mass, these three types of antivenoms have different pharmacokinetic profiles. Fab fragments have the largest volume of distribution and readily reach extravascular compartments. They are catabolised mainly by the kidney, having a more rapid clearance than F(ab')(2) fragments and IgG. On the other hand, IgG molecules have a lower volume of distribution and a longer elimination half-life, showing the highest cycling through the interstitial spaces in the body. IgG elimination occurs mainly by extrarenal mechanisms. F(ab')(2) fragments display a pharmacokinetic profile intermediate between those of Fab fragments and IgG molecules. Such diverse pharmacokinetic properties have implications for the pharmacodynamics of these immunobiologicals, since a pronounced mismatch has been described between the pharmacokinetics of venoms and antivenoms. Some venoms, such as those of scorpions and elapid snakes, are rich in low-molecular-mass neurotoxins of high diffusibility and large volume of distribution that reach their tissue targets rapidly after injection. In contrast, venoms rich in high-molecular-mass toxins, such as those of viperid snakes, have a pharmacokinetic profile characterised by a rapid initial absorption followed by a slow absorption process from the site of venom injection. Such delayed absorption has been linked with recurrence of envenomation when antibody levels in blood decrease. This heterogeneity in pharmacokinetics and mechanism of action of venom components requires a detailed analysis of each venom-antivenom system in order to determine the most appropriate type of neutralising molecule for each particular venom. Besides having a high affinity for toxicologically relevant venom components, an ideal antivenom should possess a volume of distribution as similar as possible to that of the toxins being neutralised. Moreover, high levels of neutralising antibodies should remain in blood for a relatively prolonged time to assure neutralisation of toxins reaching the bloodstream later in the course of envenomation, and to promote redistribution of toxins from extravascular compartments to blood. Additional studies are required on different venoms and antivenoms in order to further understand the pharmacokinetic-pharmacodynamic relationships of antibodies and their fragments and to optimise the immunotherapy of envenomations.
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