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Serrano-Villar S.,Hospital Universitario Ramon y Cajal and IRYCIS | Sobrino-Vegas P.,Institute Salud Carlos III | Monge S.,Institute Salud Carlos III | Dronda F.,Hospital Universitario Ramon y Cajal and IRYCIS | And 7 more authors.
Journal of Viral Hepatitis | Year: 2015

Summary While hepatitis C virus (HCV) infection seems to be expanding among HIV-infected men who have sex with men (MSM), the rate of coinfection in intravenous drug users (IDU) is assumed to remain constant. We evaluated the serial prevalence of HIV/HCV coinfection across all risk groups for HIV infection in Spain. We used data from 7045 subjects included in the multicentre, prospective Spanish Cohort of Adult HIV-infected Patients (CoRIS) between 2004 and 2011. We analysed risk factors for HIV/HCV coinfection by logistic regression analyses. The prevalence of HIV/HCV coinfection decreased from 25.3% (95% CI, 23.1-27.5) in 2004-2005 to 8.2% (95% CI, 6.9-9.5) in 2010-2011. This trend was consistently observed from 2004 to 2011 among all risk groups: IDU, 92.4% to 81.4%; MSM, 4.7% to 2.6%; heterosexual men, 13.0-8.9%; and heterosexual women, 14.5-4.0% (all P < 0.05). Strongest risk factors for HIV/HCV coinfection were IDU (OR, 54.9; 95% CI, 39.4-76.4), birth decade 1961-1970 (OR, 2.1; 95% CI, 1.1-3.7) and low educational level (OR, 2.4; 95% CI, 1.6-3.5). Hence, the prevalence of HIV/HCV coinfection decreased in Spain between 2004 and 2011. This decline was observed across all risk groups and is likely to be explained by a declining burden of HCV in the general population. © 2014 John Wiley & Sons Ltd.

PubMed | Hospital Universitario Ramon y Cajal and IRYCIS, University of Cordoba, Spain and CIBER ISCIII
Type: | Journal: Antiviral research | Year: 2015

Although an effective combination of antiretroviral therapy (cART) controls HIV-1 viraemia in infected patients, viral latency established soon after infection hinders HIV-1 eradication. It has been shown that bryostatin-1 (BRY) inhibits HIV-infection in vitro and reactivates the latent virus through the protein kinase C-NF-B pathway. We determined the in vitro potential effect of BRY in combination with currently used antiretroviral drugs. BRY alone or in combination with maraviroc (MVC)/Atripla (ATP) was tested for its capacity to reactivate latent virus and inhibit new infections. JLTRG-R5 cells and two latent HIV-1-infected cell lines, J89GFP and THP89GFP, were used as latency models. To quantify HIV infection, the reporter cell line TZM-bl was used. We found that BRY reactivates HIV-1 even in combination with MVC or ATP. Antiretroviral combinations with BRY do not interfere with BRY activity (i.e., the reactivation of latently infected cells) or with the antiviral activity of antiretroviral drugs. In addition, BRY-mediated down-modulation of surface CD4 and CXCR4 was not affected when it was used in combination with other antiretrovirals, and no hyperactivation or high-proliferation effects were observed in primary T cells. Moreover, the BRY treatment was able to reactivate HIV-1 in CD4+ T cells from HIV-1-infected patients under cART. Thus, we propose the use of BRY to purge the viral reservoir and recommend its combination with current antiretroviral treatments.

Sainz T.,Servicio Of Pediatria E Institute Investigacion Sanitaria Hospital Gregorio Maranon | Ortega-Hernandez A.,Hospital Clinico San Carlos | Serrano-Villar S.,Hospital Universitario Ramon y Cajal and IRYCIS | Navarro M.L.,Hospital General Universitario Gregorio Maranon | And 8 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

We assessed high-density lipoprotein (HDL) antiinflammatory properties in a cohort of vertically HIV-infected adolescents. We hypothesized that proatherogenic mechanisms related to inflammation and immune activation during HIV infection may impair HDL functionality and impact on the atherosclerotic burden. Compared with healthy controls, HDL from HIV-infected adolescents presented impaired functionality, as determined by its ability to inhibit monocyte chemotaxis in vitro, which correlated with detectable viral loads (P = 0.044), lower CD4 nadir (P = 0.043), increased levels of CD4 T-cell activation (P = 0.018), higher C-reactive protein (P = 0.009), and a tendency toward thicker carotid intima-media thickness (P = 0.071). Copyright © 2014 by Lippincott Williams & Wilkins.

Gutierrez C.,Hospital Universitario Ramon y Cajal and IRYCIS | Diaz L.,Hospital General Universitario Gregorio Maranon | Vallejo A.,Hospital Universitario Ramon y Cajal and IRYCIS | Hernandez-Novoa B.,Hospital Universitario Ramon y Cajal and IRYCIS | And 14 more authors.
PLoS ONE | Year: 2011

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4 + T cells in chronically HIV-1-infected patients receiving antiretroviral therapy. Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation. Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4 + or CD8 + counts, although a significant decrease was found in the proportion of HLA-DR +/CD38 + CD4 + and CD8 + T-cells. LPS and sCD14 levels increased. Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results. Trial Registration: ClinicalTrials.gov NCT00795444. © 2011 Gutiérrez, et al.

PubMed | Hospital General Universitario Gregorio Maranon, Hospital Universitario Ramon y Cajal and IRYCIS and University of Cordoba, Spain
Type: | Journal: Scientific reports | Year: 2015

Viral reactivation from latently infected cells has become a promising therapeutic approach to eradicate HIV. Due to the complexity of the viral latency, combinations of efficient and available drugs targeting different pathways of latency are needed. In this work, we evaluated the effect of various combinations of bryostatin-1 (BRY) and novel histone deacetylase inhibitors (HDACIs) on HIV-reactivation and on cellular phenotype. The lymphocyte (J89GFP) or monocyte/macrophage (THP89GFP) latently infected cell lines were treated with BRY, panobinostat (PNB) and romidepsin (RMD) either alone or in combination. Thus, the effect on the viral reactivation was evaluated. We calculated the combination index for each drug combination; the BRY/HDACIs showed a synergistic HIV-reactivation profile in the majority of the combinations tested, whereas non-synergistic effects were observed when PNB was mixed with RMD. Indeed, the 75% effective concentrations of BRY, PNB and RMD were reduced in these combinations. Moreover, primary CD4 T cells treated with such drug combinations presented similar activation and proliferation profiles in comparison with single drug treated cells. Summing up, combinations between BRY, PNB and/or RMD presented a synergistic profile by inducing virus expression in HIV-latently infected cells, rendering these combinations an attractive novel and safe option for future clinical trials.

Chen Y.,Chinese People's Liberation Army | Chen Y.,Mario Negri Institute for Pharmacological Research | Schieppati A.,Ospedali Riuniti di Bergamo | Cai G.,Chinese People's Liberation Army | And 5 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2013

Background and objectives The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed. Design, setting, participants, & measurements The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome. Results This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36-0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13-1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria. Conclusions Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations. © 2013 by the American Society of Nephrology.

Gutierrez C.,Hospital Universitario Ramon y Cajal and IRYCIS | Hernandez-Novoa B.,Hospital Universitario Ramon y Cajal and IRYCIS | Perez-Elias M.,Hospital Universitario Ramon y Cajal and IRYCIS | Moreno A.,Hospital Universitario Ramon y Cajal and IRYCIS | And 4 more authors.
HIV Clinical Trials | Year: 2013

Background: Raltegravir (RAL) constitutes the first available integrase strand transfer inhibitor (INSTI) available in clinical practice. Three independent pathways have been described to confer resistance to RAL. Secondary mutations with little effect on INSTI susceptibility and additional substitutions with an uncertain role have also been described especially in HIV-1 non-B variants. Methods: We evaluated the prevalence of primary, secondary, and additional resistance mutations to INSTIs in patients naïve to RAL or elvitegravir (EGV) carrying different HIV-1 variants. Results: A total of 83 patients infected by B HIV-1 subtype (64%) or non-B HIV-1 variants (36%) were evaluated. No primary mutations to RAL or EGV were found in the inte-grase sequences analyzed. Secondary mutations were detected in only 5 patients. Additional mutations were found in both in B and non-B variants. According to the geno2pheno algorithm, some of the secondary mutations detected (L74V, E138K, G163RS, and V151I) have been associated with a reduced estimated susceptibility to RAL and only the E138K mutation has been associated with a decreased estimated susceptibility to EGV. No virological failure was observed after RAL was administrated in 17 patients carrying 1 or more additional substitutions in the absence of primary or secondary mutations. Conclusions: No primary resistance mutations to INSTI were found in treatment-naïve or -experienced patients infected with B or non-B HIV-1 variants. The vast majority had some polymorphic and non-polymorphic substitutions; however response to RAL was excellent in patients who harbored one or more of these mutations. We could not identify any clinical factors associated with the presence of any of these mutations. © 2013 Thomas Land Publishers, Inc.

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