Cambios en las características epidemiológicas y en el pronóstico de la hepatitis crónica B en personas que viven con VIH / Epidemiological characteristic and prognosis changes in chronic hepatitis B in people living with HIV

Introducción: La vacunación, los avances en el tratamiento frente al virus de la hepatitis B (VHB) y los cambios epidemiológicos producidos en España en las últimas décadas han podido modificar las características y el pronóstico de la hepatitis crónica B (HCB) en personas que viven con VIH (PVIH). Métodos: Estudio observacional retrospectivo donde se incluyeron PVIH-HCB en seguimiento en una unidad de referencia madrileña hasta el año 2019. Se comparó la incidencia y las características epidemiológicas y clínicas según el momento del diagnóstico (antes del año 2000 y posteriormente en periodos de cinco años). Además, se realizó un estudio longitudinal retrospectivo evaluando la tasa de mortalidad, descompensación hepática y factores asociados. Resultados: De 5.452 PVIH, 160 presentaban HCB en el momento basal (prevalencia 2,92%, IC 95%: 2,5-3,4), 85,6% hombres, edad mediana al diagnóstico 32,1 (27-37,2) años. La incidencia (2,4/100 pacientes-año) no varió en los diferentes periodos. Los pacientes diagnosticados antes del 2000 (n = 87) comparados con los diagnosticados entre 2015-2019 (n = 11) con mayor frecuencia eran nativos españoles (90,8 vs. 18,2%), habían consumido drogas intravenosas (55,2 vs. 0), tenían antecedentes de hepatitis C (40 vs. 9,1%) y delta (30,4 vs. 0) y mayor afectación hepática (24,1% cirróticos vs. 0). Tras un seguimiento de 20,4 años, 23 pacientes murieron (7,1/1.000 pacientes-año) y 19 presentaron descompensación hepática (4,9/1.000 pacientes-año), todos diagnosticados antes del año 2010. La mortalidad se asoció con mayor fibrosis hepática basal estimada por Fibroscan® (HR 1,06; IC 95%: 1,03-1,09). Conclusión: Las PVIH-HCB con diagnóstico previo al año 2000 son más frecuentemente de nacionalidad española, infectadas por vía parenteral y con mayor prevalencia de otras coinfecciones. Los pacientes diagnosticados antes del 2010 tienen peor pronóstico condicionado por presentar mayor grado de fibrosis hepática.(AU)

Introduction: Due to hepatitis B virus (HBV) treatment and vaccination during the last decades in Spain, epidemiological and prognosis of chronic hepatitis B (CHB) may have changed. Methods: Retrospective review of CHB–HIV coinfected patients in a single reference center in Madrid until year 2019. We compared incidence, epidemiological and clinical characteristics according diagnosis period (before 2000, 2000–2004, 2005–2009, 2010–2014, 2015–2019). A retrospective longitudinal study was done to assess mortality, related risk factors and hepatic decompensation. Results: Out of 5452 PLHIV, 160 had CHB (prevalence 2.92%; 95% CI: 2.5–3.4), 85.6% were men, median age 32.1 (27–37.2). Incidence rate did not change over the years (2.4/100 patients-year). PLHIV with CHB diagnosed before year 2000 (n = 87) compared with those diagnosed between 2015 and 2019 (n = 11) were more often native-Spanish (90.8% vs. 18.2%), had infected using intravenous drugs (55.2% vs. 0), were coinfected with hepatitis C (40% vs. 9.1%) or hepatitis delta virus (30.4% vs. 0) and had more severe liver disease (cirrhosis 24.1% vs. 0). After a median follow-up of 20.4 years, 23 patients died (7.1/1000 patients-year) and 19 had liver decompensation (4.9/1000 patients-year). All deaths and liver decompensation occurred in patients diagnosed before year 2010. Mortality was associated with higher liver fibrosis in Fibroscan® (HR 1.06, 95% CI: 1.03–1.09). Conclusion: The epidemiology of CHB in PLHIV in our cohort is changing with less native Spanish, more sexually transmitted cases and less coinfection with other hepatotropic virus. Patients diagnosed before 2010 have worst prognosis related to higher grades of liver fibrosis.(AU)

Sex differences in the effectiveness and tolerability of dolutegravir plus rilpivirine as a switch strategy in people living with HIV.

INTRODUCTION: Dolutegravir + rilpivirine (DTG + RPV) is an effective antiretroviral therapy regimen approved in clinical guidelines as a switch therapy for virologically suppressed people with HIV. Our study aimed to compare the effectiveness and tolerability of DTG + RPV in women and men in real-world clinical practice. METHODS: This was a retrospective analysis of treatment-experienced people with HIV from a large HIV unit who switched to DTG + RPV. We analysed treatment effectiveness, rates of adverse events and discontinuation, and metabolic changes after 48 weeks of treatment. HIV-RNA levels <50 copies/mL were analysed at 48 weeks using both intention-to treat analysis (where missing data were interpreted as failures) and per-protocol analysis (excluding those with missing data or changes due to reasons other than virological failure). Outcomes were compared between women and men based on sex at birth. RESULTS: A total of 307 patients were selected (71 women and 236 men). No transgender people were included. At baseline, women had lived with HIV infection and received antiretroviral therapy for longer than men (23.2 vs 17.4 years and 18.9 vs 14.2 years, respectively). In the intention-to-treat analysis, 74.6% (95% confidence interval [CI] 63.4-83.3%) of women and 83.5% (95% CI 78.2-87.7) of men had HIV-RNA <50 copies/mL. In the per-protocol analysis, 96.4% (95% CI 87.7-99) of women and 99% (95% CI 98.9-99.7) of men had HIV-RNA levels <50 copies/mL. Two women and two men had HIV-RNA >50 copies/mL at 48 weeks. Discontinuation due to adverse events was more frequent in women than in men: 12.7% vs 7.2% (p < 0.02). Neuropsychiatric and gastrointestinal events were the most frequently reported. A median (interquartile range) weight gain of 1.9 kg (0-4.2) in women and 1.2 kg (-1-3.1) in men was reported (median of differences between baseline visit and week 48); the remaining changes in metabolic parameters were neutral. CONCLUSIONS: DTG + RPV exhibited good and similar virological effectiveness in women and men in real-world settings. However, poorer tolerability and more treatment interruptions were observed in women.

Epidemiological characteristic and prognosis changes in chronic hepatitis B in people living with HIV.

INTRODUCTION: Due to hepatitis B virus (HBV) treatment and vaccination during the last decades in Spain, epidemiological and prognosis of chronic hepatitis B (CHB) may have changed. METHODS: Retrospective review of CHB-HIV coinfected patients in a single reference center in Madrid until year 2019. We compared incidence, epidemiological and clinical characteristics according diagnosis period (before 2000, 2000-2004, 2005-2009, 2010-2014, 2015-2019). A retrospective longitudinal study was done to assess mortality, related risk factors and hepatic decompensation. RESULTS: Out of 5452 PLHIV, 160 had CHB (prevalence 2.92%; 95%CI 2.5-3.4), 85.6% were men, median age 32.1 (27-37.2). Incidence rate did not change over the years (2.4/100 patients-year). PLHIV with CHB diagnosed before year 2000 (n = 87) compared with those diagnosed between 2015 and 2019 (n = 11) were more often native-Spanish (90.8% vs. 18.2%), had infected using intravenous drugs (55.2% vs. 0), were coinfected with hepatitis C (40% vs. 9.1%) or hepatitis delta virus (30.4% vs. 0) and had more severe liver disease (cirrhosis 24.1% vs. 0). After a median follow-up of 20.4 years, 23 patients died (7.1/1000 patients-year) and 19 had liver decompensation (4.9/1000 patients-year). All deaths and liver decompensation occurred in patients diagnosed before year 2010. Mortality was associated with higher liver fibrosis in Fibroscan® (HR 1.06, 95% CI 1.03-1.09). CONCLUSION: The epidemiology of CHB in PLHIV in our cohort is changing with less native Spanish, more sexually transmitted cases and less coinfection with other hepatotropic virus. Patients diagnosed before 2010 have worst prognosis related to higher grades of liver fibrosis.

CD6 and Its Interacting Partners: Newcomers to the Block of Cancer Immunotherapies.

Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.

The T6SS-Dependent Effector Re78 of Rhizobium etli Mim1 Benefits Bacterial Competition.

The genes of the type VI secretion system (T6SS) from Rhizobium etli Mim1 (ReMim1) that contain possible effectors can be divided into three modules. The mutants in them indicated that they are not required for effective nodulation with beans. To analyze T6SS expression, a putative promoter region between the tssA and tssH genes was fused in both orientations to a reporter gene. Both fusions are expressed more in free living than in symbiosis. When the module-specific genes were studied using RT-qPCR, a low expression was observed in free living and in symbiosis, which was clearly lower than the structural genes. The secretion of Re78 protein from the T6SS gene cluster was dependent on the presence of an active T6SS. Furthermore, the expression of Re78 and Re79 proteins in E. coli without the ReMim1 nanosyringe revealed that these proteins behave as a toxic effector/immunity protein pair (E/I). The harmful action of Re78, whose mechanism is still unknown, would take place in the periplasmic space of the target cell. The deletion of this ReMim1 E/I pair resulted in reduced competitiveness for bean nodule occupancy and in lower survival in the presence of the wild-type strain.

Impact of preexisting nucleos(t)ide reverse transcriptase inhibitor resistance on the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide in treatment experience patients.

INTRODUCTION: Few clinical trials and cohort studies have evaluated the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV (PWH) with preexisting M184V/I or other nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs). Real-world data are also scarce. METHODS: Retrospective review of treatment-experienced patients who started B/F/TAF in a cohort of PWH. HIV-RNA less than 50 copies/ml was analyzed at 48 weeks in an intention-to-treat (ITT) analysis (missing=failure) and per protocol analysis (patients with missing data or changes for reasons other than virological failure were excluded). Results were compared in patients with and without previous NRTI-RAMs. RESULTS: Five hundred and six PWH were included (16.2% women). Median age and time with HIV infection were 52.3 and 18.9 years, respectively. At baseline, viral load was less than 50 copies/ml in 440 patients (86.6%). Overall, 69 (13.6%) participants had documented preexisting NRTI-RAMs: 57 (11.2%) M184V/I and 30 (5.9%) tenofovir RAMs. In the ITT analysis, 83% (420/506) had HIV-RNA less than 50 copies/ml [82.2% (359/437) and 88.4% (61/69) in persons without and with NRTI-RAMs, respectively ( P  = 0.2)]. In the per protocol analysis 94.2% (420/445) had HIV-RNA less than 50 copies/ml [94.4% (359/380) vs. 93.8% (61/65); P  = 0.2]. A total of 61 participants were excluded from the per protocol analysis (23 missing data, 19 discontinued B/F/TAF because of toxicity, 13 for other reasons, and 6 died). CONCLUSION: Switching to B/F/TAF is well tolerated and effective in the real-world setting, even in patients with preexisting NRTI RAMs, such as M184V and RAMs conferring resistance to tenofovir. These results confirm the robustness of this combination.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort.

PURPOSE: To review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades. METHODS: Retrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc. RESULTS: Out of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01-0.04) per 100 patient-year in the entire population and 0.06 (0.01-0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (ß=-0.006; p=0.047). All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis. CONCLUSION: The incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort / Hepatitis B aguda en pacientes infectados por VIH en las dos últimas décadas en una cohorte española

ObjetivoRevisar la incidencia y las características de la hepatitis B aguda (HAB), en pacientes infectados por VIH en seguimiento durante las dos últimas décadas.MétodosRevisión retrospectiva de los casos de HAB en la cohorte de pacientes infectados por VIH y seguimiento en el Hospital Universitario La Paz, entre los años 2000 y 2018. La HAB se definió como la reciente aparición del AgS frente al virus de la hepatitis B (VHB) y anticuerpos anti-HBc+ de tipo IGM.ResultadosSe siguieron 5.443 pacientes VIH+, de ellos, 3.098 sin contacto previo con el VHB (anti-HBc negativo). Diagnosticamos 18 casos de HAB, lo que supone una incidencia de 0,02 (0,01-0,04) por 100 pacientes-año en toda la población y 0,06 (0,01-0,1) por 100 pacientes-año en aquellos anti-HBc negativo. Observamos una disminución significativa en la incidencia a lo largo de los años (β = -0,006; p = 0,047).Los 18 pacientes eran hombres y la mayoría (16) tenían sexo con hombres. En cuatro casos, la HAB se produjo en pacientes vacunados sin respuesta. Quince pacientes estaban sin tratamiento frente al VIH (TAR), dos recibían TAR sin drogas frente al VHB y uno tenía TAR con lamivudina, pero no tenofovir. No observamos ninguna hepatitis B grave, pero dos pacientes (11%) desarrollaron una hepatitis crónica B.ConclusiónLa incidencia de la HAB en pacientes VIH+ en nuestro hospital es baja y ha disminuido en los últimos 20 años. Aun así, seguimos viendo casos en pacientes sin protección para el VHB: sin vacunar o vacunados sin respuesta, que no reciben tenofovir.

PurposeTo review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades.MethodsRetrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc.ResultsOut of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01–0.04) per 100 patient-year in the entire population and 0.06 (0.01–0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (β=−0.006; p=0.047).All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis.ConclusionThe incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.

Pre-Treatment with Grape Seed Extract Reduces Inflammatory Response and Oxidative Stress Induced by Helicobacter pylori Infection in Human Gastric Epithelial Cells.

Helicobacter pylori (H. pylori) is a pathogenic bacteria identified as a potential risk factor for gastritis, gastric ulcers and gastric cancer. During the stomach colonization, H. pylori triggers a strong inflammatory response and subsequent oxidative stress, which are associated with tissue damage. For this reason, it is of particular interest to develop alternative natural tools that enable modulation of the associated damaging immune response. With this purpose, we obtained grape seed extract (GSE) from sweet (not fermented) food grade seeds. The aim of our study was to investigate the effect of GSE and its two enriched procyanidins fractions (OPC and PPC) on the inflammatory process and oxidative stress produced by different H. pylori strains in human gastric epithelial cells (AGS). Anti-inflammatory activity was evaluated by measuring the level of interleukin-8 (IL-8) secretion. IL-8 production was significantly reduced in H. pylori-infected human gastric epithelial cells pre-treated with GSE or its enriched fractions when compared with non-pre-treated infected cells (from 21.6% to 87.8%). Pre-treatment with GSE or its fractions significantly decreased intracellular reactive oxygen species (ROS) production in AGS cells after infection, depending on the H. pylori strain. Our results also showed that GSE and its fractions demonstrate antibacterial activity against all strains of H. pylori used in the study. This work demonstrates the effectiveness of GSE enriched in procyanidins against the main events associated with H. pylori infection.

Acute hepatitis B among HIV positive persons: A two-decade review of cases from a Spanish cohort.

PURPOSE: To review the incidence and characteristics of acute hepatitis B (AHB) in a large cohort of HIV infected persons from a low prevalence region during the last two decades. METHODS: Retrospective review of an HIV Cohort from a single reference centre in Madrid, Spain, between 2000 and 2018. AHB was diagnosed in persons with newly acquired HBAgS and acute hepatitis with positive IgM anti-HBc. RESULTS: Out of 5443 HIV+ patients in our cohort (3098 anti-HBc negative), 18 developed AHB from 2000 to 2018. The global incidence was 0.02 (0.01-0.04) per 100 patient-year in the entire population and 0.06 (0.01-0.1) per 100 patient-year in the anti-HBc negative population. A statistically significant decrease in AHB incidence was observed during these years (ß=-0.006; p=0.047). All 18 patients diagnosed with AHB were men, the majority (16) occurred in men who have sex with men. AHB was observed in 4 persons previously unresponsive to vaccination. Regarding antiretroviral treatment (ART), 15 were not receiving ART, two persons were on ART with any HBV active drugs and one person had lamivudine in the regimen. Two persons (11%) developed chronic hepatitis B. There were no cases of fulminant hepatitis. CONCLUSION: The incidence of AHB in HIV positive persons in our cohort was low and shows a progressive decline in the last 20 years. Cases occurred in persons not protected against VHB: not vaccinated or non-responders to vaccine that were not receiving tenofovir.

Infección por Helicobacter pylori en la población VIH+: una comorbilidad en la que pensar / Helicobacter pylori infection in the HIV + population: a comorbidity to think about

INTRODUCCIÓN: Las alteraciones gastrointestinales, son frecuentes en VIH+. Helicobacter pylori puede ser una causa infradiagnosticada. MATERIAL Y MÉTODOS: Se realizó una búsqueda retrospectiva de pacientes VIH+ con infección por H. pylori entre enero de 1998 hasta diciembre de 2017. RESULTADOS: Se incluyeron 132 pacientes. La dispepsia fue la sintomatología más frecuente. Un 88,5% tuvo gastritis crónica atrófica. Se consiguió la erradicación en 102 (77,3%). La curación fue más frecuente con pauta cuádruple (p = 0,004) y en los más jóvenes (p = 0,041). CONCLUSIÓN: La infección por H. pylori podría ser responsable de manifestaciones digestivas inespecíficas en los pacientes VIH+

INTRODUCTION: Gastrointestinal disorders are frequent in HIV+. Helicobacter pylori may be an underdiagnosed cause. MATERIAL AND METHODS: Patients with HIV and H. pylori were described since January 1998 up to December 2017. RESULTS: A total de 132 patients were included. The most frequent symptom was dyspepsia. 88.5% had chronic atrophic gastritis. Eradication was achieved in 102 (77.3%). Healing was more frequent with quadruple regimen (p = 0.004) and in the youngest (p = 0.041). CONCLUSION: H. pylori infection could be responsible for nonspecific digestive manifestations in HIV + patients

The Type VI secretion system of Rhizobium etli Mim1 has a positive effect in symbiosis.

The Type VI secretion systems (T6SSs) allow bacteria to translocate effector proteins to other bacteria or to eukaryotic cells. However, little is known about the role of T6SS in endosymbiotic bacteria. In this work we describe the T6SS of Rhizobium etli Mim1, a bacteria able to effectively nodulate common beans. Structural genes and those encoding possible effectors have been identified in a 28-gene DNA region of R. etli Mim1 pRetMIM1f plasmid. Immunodetection of Hcp protein, a conserved key structural component of T6SS systems, indicates that this secretion system is active at high cell densities, in the presence of root exudates, and in bean nodules. Rhizobium etli mutants affected in T6SS structural genes produced plants with lower dry weight and smaller nodules than the wild-type strain, indicating for the first time that the T6SS plays a positive role in Rhizobium-legume symbiosis.

Switching from tenofovir containing regimens to boosted protease inhibitor monotherapy: Impact on renal function / Simplificación a monoterapia con inhibidores de la proteasa potenciados desde regímenes con tenofovir: impacto en la función renal

OBJECTIVE: To evaluate the effect on creatinine clearance (CG-CrCl, Cockcroft-Gault equation) of switching to boosted protease inhibitor (PI) monotherapy in patients receiving a triple drug antiretroviral regimen containing TDF. METHODS: All patients who had received a TDF-containing regimen for at least one year and had been switched to PI monotherapy were included. A rapid decrease in CG-CrCl during exposure to TDF was defined as a decrease in CG-CrCl at least five times higher than the expected due to age (0.4 ml/min/year by the years of exposure to TDF). In this subgroup of patients, we considered improvement if the last value of CG-CrCl on PI monotherapy was 10% higher than the last value of CG-CrCl before switching to PI monotherapy. A multivariate logistic regression was constructed to identify factors associated to renal improvement after switching to bPI monotherapy. RESULTS: 64 patients included. The median (IQR) annual change in CG-CrCl during PI monotherapy was significantly lower than the median (IQR) annual change while exposed to TDF [−0.9 (−4.7 to +2.8) ml/min vs. −4 (−8 to −1) ml/min, p = 0.001]. 44 patients experienced a rapid decline during TDF exposition. After switch to PI monotherapy, 15/44 (34%, 95% CI: 21-50%) had an improved CG-CrCl and 16/44 (36%, CI 23-52%) experienced a further decline in CG-CrCl. The only variable associated to CG-CrCl improvement was a more rapid CG-CrCl decline in the last year of exposure to TDF. CONCLUSION: Switching to PI monotherapy partially reversed CG-CrCl decrease associated to TDF use, especially in patients with a more rapid decline while receiving TDF

OBJETIVO: Evaluar el efecto de la retirada de TDF en el aclaramiento de creatinina medido mediante la fórmula de Cockcroft-Gault (CG-ClCr) en pacientes que simplifican a monoterapia con un inhibidor de la proteasa (IP) potenciado. MÉTODOS: Se incluyeron todos los pacientes que habían recibido un regimen con TDF durante al menos un año y que posteriormente habían sido simplificados a monoterapia. Se definió como rápida disminución del CG-CrCl durante la exposición a TDF a una disminución del CG-CrCl de al menos 5 veces mayor de lo esperado para la edad (0.4 ml/min/año por los años de exposición al TDF). En este subgrupo de pacientes, se consideró mejoría si el último valor del CG-CrCl durante la exposición a monoterapia era un 10% más alto que el último valor de CG-CrCl antes de la simplificación. Se construyó una regresión logística multivariante para identificar los factores asociados a mejoría del CG-ClCr. RESULTADOS: Se incluyeron 64 pacientes. La mediana del cambio anual en el CG-CrCl durante la exposición a monoterapia fue significativamente inferior a la mediana del cambio anual durante la exposición a TDF (p = 0.001). 44 pacientes presentaron una rápida disminución del CG-CrCl durante la exposición a TDF. Después de la simplificación, 15/44 (34%, IC 95%: 21-50%) presentaron una mejoría del CG-CrCl y 16/44 (36%, IC 23-52%) continuaron con un empeoramiento en el CG-CrCl. La única variable asociada con mejoría fue haber presentado una disminución más rápida del CG-CrCl en el último año de exposición a TDF. CONCLUSIÓN: La simplificación a monoterapia revierte parcialmente la disminución del CG-CrCl asociada al TDF, especialmente en los pacientes que presentan una disminución más rápida durante la exposición a TDF

Switching from tenofovir containing regimens to boosted protease inhibitor monotherapy: Impact on renal function.

OBJECTIVE: To evaluate the effect on creatinine clearance (CG-CrCl, Cockcroft-Gault equation) of switching to boosted protease inhibitor (PI) monotherapy in patients receiving a triple drug antiretroviral regimen containing TDF. METHODS: All patients who had received a TDF-containing regimen for at least one year and had been switched to PI monotherapy were included. A rapid decrease in CG-CrCl during exposure to TDF was defined as a decrease in CG-CrCl at least five times higher than the expected due to age (0.4ml/min/year by the years of exposure to TDF). In this subgroup of patients, we considered improvement if the last value of CG-CrCl on PI monotherapy was 10% higher than the last value of CG-CrCl before switching to PI monotherapy. A multivariate logistic regression was constructed to identify factors associated to renal improvement after switching to bPI monotherapy. RESULTS: 64 patients included. The median (IQR) annual change in CG-CrCl during PI monotherapy was significantly lower than the median (IQR) annual change while exposed to TDF [-0.9 (-4.7 to +2.8) ml/min vs. -4 (-8 to -1) ml/min, p=0.001]. 44 patients experienced a rapid decline during TDF exposition. After switch to PI monotherapy, 15/44 (34%, 95% CI: 21-50%) had an improved CG-CrCl and 16/44 (36%, CI 23-52%) experienced a further decline in CG-CrCl. The only variable associated to CG-CrCl improvement was a more rapid CG-CrCl decline in the last year of exposure to TDF. CONCLUSION: Switching to PI monotherapy partially reversed CG-CrCl decrease associated to TDF use, especially in patients with a more rapid decline while receiving TDF.

The natural history of liver cirrhosis in HIV-hepatitis C virus-coinfected patients.

OBJECTIVE: To provide detailed information about the natural history of HIV-hepatitis C virus (HCV)-coinfected patients with cirrhosis. METHODS: Prospective cohort including 340 HIV-HCV-coinfected patients with compensated (n = 248) or decompensated (n = 92) cirrhosis. We evaluated predictors of survival and of first hepatic decompensation. RESULTS: The mortality rate for patients with decompensated and compensated cirrhosis was 27.14 deaths per 100 person-years [95% confidence interval (CI) 18.93-35.35] and 3.98 deaths per 100 person-years (95% CI 2.42-5.54), respectively. Rate of first hepatic decompensation in patients with compensated cirrhosis was 4.62 per 100 persons-years (95% CI 2.91-6.33). In the complete cohort, permanent HAART interruption during follow-up, CD4 cell count nadir and baseline Child-Pugh score (CPS) B or C were significantly associated with shorter survival. In patients with compensated cirrhosis factors significantly associated with decreased survival were having the first hepatic decompensation during follow-up, permanent HAART discontinuation, and CPS B and C at baseline. For patients with compensated cirrhosis, time since diagnosis of HCV infection, CPS B and C and permanent HAART discontinuation were significantly associated with the risk of first hepatic decompensation. Sustained viral response to anti-HCV therapy was not independently associated with better survival in patients with compensated cirrhosis. CONCLUSION: HIV-HCV-coinfected patients with cirrhosis have a relatively good 3-year survival (87%). In contrast, 2-year survival of patients with decompensated liver cirrhosis is only 50%. Three-year survival was mostly impacted by liver-related factors and HAART maintenance.

PPARß/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.

Owing to its high fat content, the classical Western diet has a range of adverse effects on the heart, including enhanced inflammation, hypertrophy, and contractile dysfunction. Proinflammatory factors secreted by cardiac cells, which are under the transcriptional control of nuclear factor-κB (NF-κB), may contribute to heart failure and dilated cardiomyopathy. The underlying mechanisms are complex, since they are linked to systemic metabolic abnormalities and changes in cardiomyocyte phenotype. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolism and are capable of limiting myocardial inflammation and hypertrophy via inhibition of NF-κB. Since PPARß/δ is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPARß/δ agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-κB in the heart of mice. GW501516 abrogated this enhanced proinflammatory profile. Similar results were obtained when human cardiac AC16 cells exposed to palmitate were coincubated with GW501516. PPARß/δ activation by GW501516 enhanced the physical interaction between PPARß/δ and p65, which suggests that this mechanism may also interfere NF-κB transactivation capacity in the heart. GW501516-induced PPARß/δ activation can attenuate the inflammatory response induced in human cardiac AC16 cells exposed to the saturated fatty acid palmitate and in mice fed a high-fat diet. This is relevant, especially taking into account that PPARß/δ has been postulated as a potential target in the treatment of obesity and the insulin resistance state.

The Role of Peroxisome Proliferator-Activated Receptor beta/delta on the Inflammatory Basis of Metabolic Disease.

The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases.

Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome.

Metabolic syndrome is defined as the clustering of multiple metabolic abnormalities, including abdominal obesity, dyslipidemia (high serum triglycerides and low serum HDL-cholesterol levels), glucose intolerance and hypertension. The pathophysiology underlying metabolic syndrome involves a complex interaction of crucial factors, but two of these, insulin resistance and obesity (especially visceral obesity), play a major role. The nuclear receptors Peroxisome Proliferator-Activated Receptors (PPAR)alpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively. Evidence is now emerging that the PPARbeta/delta; isotype is a potential pharmacological target for the treatment of disorders associated with metabolic syndrome. PPARbeta/delta; activation increases lipid catabolism in skeletal muscle, heart and adipose tissue and improves the serum lipid profile and insulin sensitivity in several animal models. In addition, PPARbeta/delta; ligands prevent weight gain and suppress macrophage-derived inflammation. These data are promising and indicate that PPARbeta/delta; ligands may become a therapeutic option for the treatment of metabolic syndrome. However, clinical trials in humans assessing the efficacy and safety of these drugs should confirm these promising perspectives in the treatment of the metabolic syndrome.

PPARbeta/d reduce la expresión de citocinas inflamatorias en adipocitos mediante la inhibición de NF-?B

Introducción y objetivo: La resistencia a la insulina se relaciona con la presencia de un proceso inflamatorio de baja intensidad, caracterizado por la activación crónica del factor nuclear kappa B (NF-kB) y la producción de citocinas proinflamatorias en tejido adiposo blanco. Recientemente, se ha propuesto que el receptor activado por proliferadores peroxisómicos beta/d (PPAR beta/d) puede llegar a convertirse en una diana para el tratamiento de la resistencia a la insulina. Sin embargo, se desconoce si la activación de este receptor nuclear previene el proceso inflamatorio en adipocitos. Metodos y resultados: La activación de PPAR beta/d por un ligando específico, GW501516, evitó el aumento en la expresión y la secreción de interleucina (IL) 6 inducida por lipopolisacárido (LPS) en adipocitos 3T3-L1. Este efecto se asoció con la capacidad del agonista de PPAR beta/d para inhibir la activación del NF-kB inducida por LPS. Por otro lado, la expresión de IL-6 y la actividad del NF-?B estaban incrementadas en el tejido adiposo de ratones PPAR beta/d-/-, en comparación con ratones wild-type, hecho que indica que este receptor regula la activación de NF-?B y de sus genes diana. Puesto que se ha relacionado la activación de la vía ERK1/2 con la activación de NF-kB, determinamos el efecto de PPAR beta/d en la activación de esta vía. El tratamiento con GW501516 evitó la fosforilación de ERK1/2 inducida por LPS, mientras que el tejido adiposo blanco de ratones PPAR beta/d-/- mostró un incremento considerable en los valores de fosforilación de esta cinasa. Conclusiones: Estos resultados parecen indicar que la activación de PPAR beta/d bloquea el incremento de la producción de citocinas inflamatorias en adipocitos mediante la prevención de la activación de NF-kB por ERK1/2. Esta acción de PPAR beta/d puede contribuir a prevenir la resistencia a la insulina (AU)

Introduction and objective: Insulin resistance is associated with a low-grade systemic inflammatory response characterized by NF-kB activation and pro-inflammatory cytokine production from white adipose tissue. Recently PPAR beta/d has been proposed as a potential treatment for insulin resistance. However, it is presently unknown whether PPAR beta/d activation prevents this process in adipocytes. Methods and results: PPAR beta/d activation by GW501516 blocked LPS-induced IL-6 expression and secretion by 3T3-L1 adipocytes. This effect was associated with the capacity of GW501516 to prevent LPS-induced NF-kB activation. In addition, IL-6 expression and NF-kB DNA-binding activity was higher in white adipose tissue from PPAR beta/d-null mice than in wild-type mice, fact that suggests that this receptor regulates NF-kB activation and its target genes. Since the ERK1/2 pathway has been involved in NF-kB activation, we explored the effect of PPAR beta/d activation on this pathway. GW501516 treatment prevented ERK1/2-phosphorylation by LPS, whereas white adipose tissue from PPAR beta/d-null mice showed increased phospho-ERK1/2 levels. Conclusions: These findings indicate that PPAR beta/d activation blocks enhanced cytokine production in adipocytes by preventing NF-kB activation via ERK1/2. This PPAR beta/d effect may contribute to prevent insulin resistance (AU)

Atorvastatin prevents carbohydrate response element binding protein activation in the fructose-fed rat by activating protein kinase A.

UNLABELLED: High fructose intake contributes to the overall epidemic of obesity and metabolic disease. Here we examined whether atorvastatin treatment blocks the activation of the carbohydrate response element binding protein (ChREBP) in the fructose-fed rat. Fructose feeding increased blood pressure (21%, P < 0.05), plasma free fatty acids (59%, P < 0.01), and plasma triglyceride levels (129%, P < 0.001) compared with control rats fed standard chow. These increases were prevented by atorvastatin. Rats fed the fructose-rich diet showed enhanced hepatic messenger RNA (mRNA) levels of glycerol-3-phosphate acyltransferase (Gpat1) (1.45-fold induction, P < 0.05), which is the rate-limiting enzyme for the synthesis of triglycerides, and liver triglyceride content (2.35-fold induction, P < 0.001). Drug treatment inhibited the induction of Gpat1 and increased the expression of liver-type carnitine palmitoyltransferase 1 (L-Cpt-1) (128%, P < 0.01). These observations indicate that atorvastatin diverts fatty acids from triglyceride synthesis to fatty acid oxidation, which is consistent with the reduction in liver triglyceride levels (28%, P < 0.01) observed after atorvastatin treatment. The expression of Gpat1 is regulated by ChREBP and sterol regulatory element binding protein-1c (SREBP-1c). Atorvastatin treatment prevented fructose-induced ChREBP translocation and the increase in ChREBP DNA-binding activity while reducing SREBP-1c DNA-binding activity. Statin treatment increased phospho-protein kinase A (PKA), which promotes nuclear exclusion of ChREBP and reduces its DNA-binding activity. Human HepG2 cells exposed to fructose showed enhanced ChREBP DNA-binding activity, which was not observed in the presence of atorvastatin. Furthermore, atorvastatin treatment increased the CPT-I mRNA levels in these cells. Interestingly, both effects of this drug were abolished in the presence of the PKA inhibitor H89. CONCLUSION: These findings indicate that atorvastatin inhibits fructose-induced ChREBP activity and increases CPT-I expression by activating PKA.