Bonaventura Clotet

IrsiCaixa Institute for AIDS Research, Badalona, Catalonia, Spain

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Publications (652)

  • Carmina R. Fumaz · Aintzane Ayestaran · Nuria Perez-Alvarez · [...] · Bonaventura Clotet
    [Show abstract] [Hide abstract] ABSTRACT: The prevalence and associated factors of erectile dysfunction (ED) in Human Immunodeficiency Virus (HIV)–infected men remain controversial. The authors evaluated ED, clinical, and emotional variables in a group of 501 HIV-infected men in a cross-sectional 4-month observational study. ED was assessed using the International Index of Erectile Function–5 and emotional status using the Hospital Anxiety and Depression (HAD) questionnaire. Median age (interquartile range) was 42 (35, 48) years. Time since HIV diagnosis was 6.3 (2.6, 17.1) years, 92% were taking antiretroviral treatment and 81.8% had an HIV-RNA viral load <50 copies. The prevalence of ED was 58.5%. ED was mild in 30.1%, mild to moderate in 19.5%, moderate in 6.1%, and severe in 2.5%. ED medications were used by 19% of men. In the univariate analysis, the variables associated with all degrees of ED were older age, longer time since HIV diagnosis, higher scores in HAD, not taking efavirenz, taking etravirine, taking ritonavir, HIV/Hepatitis C Virus coinfection, and taking a protease inhibitor-containing regimen. For mild to moderate, moderate, and severe ED, the same variables were significant, as were lower nadir CD4 cell count, lower social support, taking atazanavir, concomitant conditions, and concomitant treatments. The variables that remained significant in the multivariate analyses, considering all degrees of ED or excluding mild ED were the following: older age and higher scores in HAD total. In summary, ED affected more than half of this cohort of well controlled HIV-infected men. Age and emotional status seemed to play a fundamental role in its presence.
    Article · Sep 2016 · American Journal of Men s Health
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    Dataset: S3 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Mouse peritoneal macrophages resemble GM-CSF expression profile. (A) Comparative gene expression of cell cycle-related genes and SAMHD1 in mouse peritoneal macrophages and human M-CSF and GM-CSF macrophages. mRNA levels of CCND2, CCND3, CDK2, CDK4, SAMHD1 and the CDK inhibitors p21 (CDKN1A) and p27 (CDKN1B) were quantified by real time PCR. Relative expression of each gene vs. GAPDH is plotted. Horizontal bars represent mean values. * p<0.05; ** p<0.005; *** p<0.0005; ns, not significant. (B) Western blot showing protein expression in peritoneal macrophages from 3 different mice. Mice protein expression was compared to different protein concentrations of GM-CSF and M-CSF human macrophages in order to evaluate the relative levels of expression for each sample. (TIFF)
    File available · Dataset · Aug 2016
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    Dataset: S4 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Cyclin D2 restricts HIV-1 replication and proviral DNA formation in GM-CSF macrophages. (A) SAMHD1 expression levels after knockdown of CCND2 and CCND3 expression by siRNA. Relative mRNA expression of SAMHD1 in M-CSF (white bars) and GM-CSF (black bars) macrophages. SAMHD1 mRNA was measured by quantitative PCR and normalized to GAPDH expression. Data represents mean ± SD of 3 different donors and is normalized to Mock-transfected M-CSF macrophages. (B) Effective knockdown of CCND2 expression with two different siRNA sequences (siCCND2#1 and siCCND2#2). CCND2 mRNA was measured by quantitative PCR and normalized to GAPDH expression. Data represents mean ± SD of 3 different donors and is normalized to Mock-transfected macrophages. (C) HIV-1 replication in siCCND2 GM-CSF macrophages. Transfected MDM were infected with a VSV-pseudotyped, GFP-expressing HIV-1 and infection measured 72h later by flow cytometry. Data represent percentage replication relative to mock-transfected macrophages. Mean ± SD of 3 different donors performed in duplicate is shown. (D) Proviral DNA formation after 16h infection with HIV-1 BaL of GM-CSF macrophages transfected with the indicated siCCND2 sequences or treated with AZT (3 μM) or raltegravir (RAL; 2 μM). Proviral DNA was normalized to mock-treated macrophages. Mean ± SD of 3 different donors is shown. * p<0.05; ** p<0.005; *** p<0.0005. (TIFF)
    File available · Dataset · Aug 2016
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    Dataset: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Phenotypic characterization of M-CSF and GM-CSF macrophages. (A) Summary of cell surface antigens expression. Markers of macrophage differentiation, HIV-1 receptor and coreceptors and cell activation and proliferation markers were evaluated by flow cytometry. The table shows mean ± SD of at least 3 different donors. nd, not detected. (B) Intracellular dNTP levels in M-CSF or GM-CSF differentiated MDM. Intracellular dNTPs were extracted from M-CSF (left) or GM-CSF (right) differentiated MDM and dNTP content was determined using a polymerase-based method. dNTP content is highly variable between donors and therefore data is relativized to M-CSF differentiated MDM. Mean ± SD of 3 different donors is shown. * p<0.05 (TIFF)
    File available · Dataset · Aug 2016
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    Dataset: S2 Fig
    [Show abstract] [Hide abstract] ABSTRACT: GM-CSF macrophages cultured with human serum (HS) or fetal bovine serum (FBS) show lower proliferation rates, higher expression of cyclin D2 and are less susceptible to HIV-1 infection compared to M-CSF. (A) Evaluation of cell proliferation by Ki67 staining. Histograms of a representative donor showing Ki67 staining in M-CSF and GM-CSF derived macrophages either with HS or FBS. Percentage of positive cells is shown in each case. (B) Dot plots representing cell cycle profile showing DNA (7-AAD) and RNA (Pyronin Y) content of M-CSF and GM-CSF differentiated macrophages cultured with HS or FBS and quantified by flow cytometry. Data from a representative donor is shown. (C) Gene expression of cell cycle-related genes and SAMHD1 restriction pathway. mRNA levels of SAMHD1, CDK2, CDK4 and CDK6, all D-type cyclins (D1, D2 and D3) and the CDK inhibitors p21 (CDKN1A) and p27 (CDKN1B) was quantified in M-CSF, human serum (white bars) and M-CSF, FBS (black bars), GM-CSF, human serum (light grey bars) and GM-CSF, FBS (dark grey bars) differentiated macrophages. Data is normalized to M-CSF, FBS relative expression. Mean ± SD of 3 independent donors is shown. ** p<0.005; *** p<0.0005. (D) Western blot showing protein expression of different cell cycle proteins, SAMHD1 expression and activation and Hsp90 as loading control. A representative donor is shown. M; M-CSF MDM, GM; GM-CSF MDM. (E) HIV-1 replication in M-CSF MDM and GM-CSF MDM cultured with human serum (white bars) or fetal bovine serum (FBS) (black bars). Data represent percentage replication relative to M-CSF culture with FBS. Mean ± SD of 3 different donors performed in triplicate is shown. ** p<0.005; *** p<0.0005 (TIFF)
    File available · Dataset · Aug 2016
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    Dataset: S5 Fig
    [Show abstract] [Hide abstract] ABSTRACT: Knockdown of cyclin D2 does not affect macrophage function. (A) Cytokine expression in GM-CSF siRNA-treated macrophages. Cytokine mRNA expression was measured using a TaqMan Human Cytokine Network array and expression of each gene was normalized to GAPDH. Data is normalized to Mock-transfected macrophages. Mean ± SD of 2 different donors performed in duplicate is shown. (B) Induction of cytokine gene expression following LPS (100 ng/ml) treatment in siCCND2 GM-CSF macrophages. mRNA expression of CCL-2 and IL-10 was measured by quantitative PCR and normalized to GAPDH expression. Data is normalized to untreated Mock-transfected GM-CSF macrophages. A representative donor is shown. (TIFF)
    File available · Dataset · Aug 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Author Macrophages are a heterogeneous population of immune cells that provide crucial innate immune defense against pathogens, including HIV-1. The molecular biology of HIV-1 infection in macrophages is influenced by the presence of the host cell restriction factor SAMHD1, which is regulated by phosphorylation by cyclin dependent kinases, the catalytic proteins responsible for cell cycle progression. This study shows that differentiation stimuli strongly influence macrophage cell cycle and proliferation characteristics as well as susceptibility to HIV-1 infection through modulation of SAMHD1 activation. We have identified cyclin D2 as the key step controlling susceptibility to HIV-1 infection by modulation of the signaling pathway leading to SAMHD1 phosphorylation. We show that a complex formed by cyclin D2-CDK4-p21 in GM-CSF macrophages is responsible for the lack of the active CDK, which phosphorylates SAMHD1. This situation is reversed in the absence of cyclin D2, leading to the activation of CDKs and subsequent phosphorylation of its substrates, including SAMHD1. Thus, we propose that the differential expression of the G1/S-specific cyclin D2 controls the HIV-1 restriction pathway in primary macrophages.
    Full-text available · Article · Aug 2016 · PLoS Pathogens
  • [Show abstract] [Hide abstract] ABSTRACT: Background In most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. However, even after years of effective treatment, a significant proportion of patients show residual plasma viremia below the clinical detection limit. Although residual viremia might be associated with increased chronic immune activation and morbidity, its origin and its potential role in the replenishment of the viral reservoir during suppressive ART is not completely understood. We performed an in-depth genetic analysis of the total and episomal cell-associated viral DNA (vDNA) repertoire in purified CD4+ T cell subsets of three HIV-infected individuals, and used phylogenetic analysis to explore its relationship with plasma viruses. Results The predominant proviral reservoir was established in naïve or memory (central and transitional) CD4+ T cell subsets in patients harboring X4- or R5-tropic viruses, respectively. Regardless of the viral tropism, most plasma viruses detected under suppressive ART resembled the proviral reservoir identified in effector and transitional memory CD4+ T-cell subsets in blood, suggesting that residual viremia originates from these cells in either blood or lymphoid tissue. Most importantly, sequences in episomal vDNA in CD4+ T-cells were not well represented in residual viremia. Conclusions Viral tropism determines the differential distribution of viral reservoir among CD4+ T-cell subsets. In spite of viral tropism, the effector and transitional memory CD4+ T-cells subsets are the main source of residual viremia during suppressive ART, even though their contribution to the total proviral pool is small. However, the lack of concordance between residual viremia and viral variants driving de novo infection of CD4+ T cells on ART may reflect the predominance of defective plasma HIV RNA genomes. These findings highlight the need for monitoring the multiple viral RNA/DNA persistence markers, based on their differential contribution to viral persistence. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0282-9) contains supplementary material, which is available to authorized users.
    Article · Aug 2016 · Retrovirology
  • [Show abstract] [Hide abstract] ABSTRACT: HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10. Infected macrophages showed increased expression of p21 and subsequent inactivation of cyclin-CDK2 activity leading to a hypo-phosphorylated active retinoblastoma protein (pRb) and deactivation of E2F1-dependent transcription and CDK1 downregulation. Additionally, HIV-1 infection limited deoxynucleotide pool by downregulation of the ribonucleotide reductase subunit R2 (RNR2) and reactivation of the HIV-1 restriction factor SAMHD1 together with increased cell death. In conclusion, HIV-1 induced an innate antiviral mechanism associated to IFN-I production, interferon stimulated gene activation, and p21-mediated G2/M arrest leading to elevated levels of cell death in monocyte derived macrophages. Upregulation of MDA5 and Rig-I may serve as targets for the development of antiviral strategies leading to the elimination of HIV-1 infected cells.
    Article · Aug 2016 · Antiviral research
  • [Show abstract] [Hide abstract] ABSTRACT: Kidney injury (defined as the presence of albuminuria, proteinuria, glycosuria [without hyperglycemia], hematuria, and/or renal hypophosphatemia) is an emerging problem in human immunodeficiency virus (HIV)-infected patients, although few data are available on the role of protease inhibitors (PIs) in this condition.To determine the time to kidney injury in a cohort of HIV-infected patients receiving a PI-containing regimen.We report the results of a subanalysis of a published cross-sectional study. The subanalysis included only patients receiving PI-containing regimens for more than 6 months (377 of the overall 970 patients). We determined associated factors and constructed receiver operating characteristic curves to estimate time to kidney injury depending on the PI used.The percentage of patients with kidney injury was 27.7% for darunavir, 27.9% for lopinavir, and 30% for atazanavir. Time to kidney injury was as follows: 229 days for atazanavir/ritonavir (area under the curve [AUC], 0.639; sensitivity, 0.89; specificity, 0.41); 332 days for atazanavir/ritonavir plus tenofovir (AUC, 0.603; sensitivity, 0.75; and specificity, 0.29); 318 days for nonboosted atazanavir (AUC, 0.581; sensitivity, 0.89; and specificity, 0.29); 478 days for lopinavir/ritonavir (AUC, 0.566; sensitivity, 0.864; and specificity, 0.44); 1339 days for lopinavir/ritonavir plus tenofovir (AUC, 0.667; sensitivity, 0.86; and specificity, 0.77); 283 days for darunavir/ritonavir (AUC, 0.523; sensitivity, 0.80; and specificity, 0.261); and 286 days for darunavir/ritonavir plus tenofovir (AUC, 0.446; sensitivity, 0.789; and specificity, 0.245). The use of lopinavir/ritonavir without tenofovir was a protective factor (odds ratio = 1.772; 95%CI, 1.070-2.93; P = 0.026).For all PIs, the percentage of patients with kidney injury exceeded 27%, irrespective of tenofovir use. The longest time to kidney injury was recorded with lopinavir/ritonavir. These results demonstrate the need for renal monitoring, including urine samples, in patients receiving a PI-based regimen, even when tenofovir is not used concomitantly.
    Article · Aug 2016 · Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Objective: To evaluate the efficiency of single-tablet regimens (STR) and multiple-tablet regimens (MTR) with exactly the same or different components. Methods: A study was conducted on HIV-1-infected antiretroviral-naïve patients from 6 Spanish or French centers, who were started on treatment with STR-Atripla(®), or the same components separately (MTR-SC), or a different MTR (MTR-Other). Effectiveness was measured as percentage of HIV-RNA <50copies/mL at 48 weeks (ITT). Efficiency was the ratio between costs (direct cost of antiretrovirals plus outpatient visits, hospital admissions, and resistance tests) and effectiveness. Results: The study included a total of 2773 patients (759 STR-Atripla(®), 483 MTR-SC, and 1531 MTR-Other). Median age was 37 years, 15% were HCV co-infected, 27% had a CD4+ count <200cells/μL, and 30% had viral load ≥100.000copies/mL. The duration of the assigned treatment was longer for STR-Atripla(®) (P<.0001). Response rates (adjusted for CD4+ count, viral load, and clustered on hospitals) at 48 weeks were 76%, 74%, and 62%, respectively (P<.0001). Virological failure was more common in MTR patients (P=.0025), and interruptions due to intolerance with MTR-Other (P<.0001). Cost per responder at 48 weeks (efficiency) was €12,406 with STR-Atripla(®), €11,034 with MTR-SC (0.89 [0.82, 0.99] times lower), and €18,353 (1.48 [1.38, 1.61] times higher) with MTR-Other. Conclusions: STR-Atripla(®) and MTR-SC regimens showed similar effectiveness, but virological failure rate was lower with STR-Atripla. MTR-SC, considered less convenient, had a marginally better efficiency, mainly due to lower direct costs. MTR-Other regimens had both a worse effectiveness and efficiency. Similar efficiency analyses adjusting for baseline characteristics should be recommended for new STRs.
    Full-text available · Article · Aug 2016 · Enfermedades Infecciosas y Microbiología Clínica
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    [Show abstract] [Hide abstract] ABSTRACT: Importance: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The non-human TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+ T cell-mediated inhibition through the direct activation of HIV-1-specific CD8+ T-cell responses. We found that the potency in CD8+ activation was stronger for RhT5 variants and capsid-specific CD8+ T-cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection.
    Full-text available · Article · Jul 2016 · Journal of Virology
  • [Show abstract] [Hide abstract] ABSTRACT: Importance: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. Objective: To evaluate the rate of within-couple HIV transmission (heterosexual and men who have sex with men [MSM]) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/mL. Design, setting, and participants: The prospective, observational PARTNER (Partners of People on ART-A New Evaluation of the Risks) study was conducted at 75 clinical sites in 14 European countries and enrolled 1166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex (September 2010 to May 2014). Eligibility criteria for inclusion of couple-years of follow-up were condomless sex and HIV-1 RNA load less than 200 copies/mL. Anonymized phylogenetic analysis compared couples' HIV-1 polymerase and envelope sequences if an HIV-negative partner became infected to determine phylogenetically linked transmissions. Exposures: Condomless sexual activity with an HIV-positive partner taking virally suppressive ART. Main outcomes and measures: Risk of within-couple HIV transmission to the HIV-negative partner. Results: Among 1166 enrolled couples, 888 (mean age, 42 years [IQR, 35-48]; 548 heterosexual [61.7%] and 340 MSM [38.3%]) provided 1238 eligible couple-years of follow-up (median follow-up, 1.3 years [IQR, 0.8-2.0]). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5-6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15-71), with MSM couples reporting approximately 22 000 condomless sex acts and heterosexuals approximately 36 000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple-years of follow-up. Conclusions and relevance: Among serodifferent heterosexual and MSM couples in which the HIV-positive partner was using suppressive ART and who reported condomless sex, during median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission (upper 95% confidence limit, 0.30/100 couple-years of follow-up). Additional longer-term follow-up is necessary to provide more precise estimates of risk.
    Article · Jul 2016 · JAMA The Journal of the American Medical Association
  • [Show abstract] [Hide abstract] ABSTRACT: Aims: The aim of the present study was to develop a simultaneous population pharmacokinetic model for atazanavir (ATV) incorporating the effect of ritonavir (RTV) on clearance to predict ATV concentrations under different dosing regimens in HIV-1-infected patients. Methods: A Cross-sectional study was carried out in 83 HIV-1-infected adults taking ATV 400 mg or ATV 300 mg/RTV 100 mg once daily. Demographic and clinical characteristics were registered and blood samples collected to measure drug concentrations. A population pharmacokinetic model was constructed using nonlinear mixed-effects modelling and used to simulate six dosing scenarios. Results: The selected one-compartmental model described the pharmacokinetics of RTV and ATV simultaneously, showing exponential, direct inhibition of ATV clearance according to the RTV plasma concentration, which explained 17.5% of the variability. A mean RTV plasma concentration of 0.63 mg l(-1) predicted an 18% decrease in ATV clearance. The percentages of patients with an end-of-dose-interval concentration of ATV below or above the minimum and maximum target concentrations of 0.15 mg l(-1) and 0.85 mg l(-1) favoured the selection of the simulated ATV/RTV once-daily regimens (ATV 400 mg, ATV 300 mg/RTV 100 mg, ATV 300 mg/RTV 50 mg, ATV 200/RTV 100 mg) over the unboosted twice-daily regimens (ATV 300 mg, ATV 200 mg). Conclusions: A one-compartment simultaneous model can describe the pharmacokinetics of RTV and ATV, including the effect of RTV plasma concentrations on ATV clearance. This model is promising for predicting individuals' ATV concentrations in clinical scenarios, and supports further clinical trials of once-daily doses of ATV 300 mg/RTV 50 mg or ATV 200 mg/RTV 100 mg to confirm efficacy and safety.
    Article · Jul 2016 · British Journal of Clinical Pharmacology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: The failure to increase CD4 T-cell counts in some ART-suppressed subjects (immunodiscordance) has been related to perturbed CD4 T-cell homeostasis and impacts clinical evolution. Methods: We evaluated different definitions of immunodiscordance based on CD4 T-cell counts (cutoff) or CD4 T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 ART-suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals. Results: Cutoff definition of 400 CD4 cells/μL performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 T-cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated subjects into three distinct subgroups with distinct production, PD-1 expression, activation and death of T-cells. Surprisingly, a non-negligible number of immunodiscordant subjects (22%) showed high frequency of recent thymic emigrants and low CD4 T-cell activation and death, very similar to immunoconcordant subjects. Notably, HLA-DR, PD-1 and CD45RA expression in CD4 T-cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 values were maintained in these subjects overtime. Conclusions: A cutoff value of 400 CD4 T cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 T-cell recovery.
    Article · Jul 2016 · AIDS
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    [Show abstract] [Hide abstract] ABSTRACT: Objectives To evaluate the role of P-glycoprotein (P-gp) and multidrug-resistant-protein 1 (MRP1) on raltegravir intracellular drug disposition in CD4+ T cells, investigate the effect of HIV-1 infection on P-gp expression and correlate HIV-1 viraemia with P-gp activity in primary CD4+ T cell subsets. Methods The cellular accumulation ratio of [3H]raltegravir was quantified in CD4+ T cell lines overexpressing either P-gp (CEM-P-gp) or MRP1 (CEM-MRP1) and in primary CD3+CD4+ T cells with high (P-gphigh) and low P-gp activity (P-gplow); inhibition of efflux transporters was confirmed by the intracellular retention of calcein-AM. The correlation of P-gp activity with HIV-1 viraemia was assessed in naive and memory T cell subsets from 21 HIV-1-infected treatment-naive subjects. Results [3H]Raltegravir cellular accumulation ratio decreased in CEM-P-gp cells (P
    Full-text available · Article · Jun 2016 · Journal of Antimicrobial Chemotherapy
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    [Show abstract] [Hide abstract] ABSTRACT: Background: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/μL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. Methods: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. Results: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. Conclusions: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.
    Full-text available · Article · Apr 2016 · Clinical Infectious Diseases
  • Article · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The design and selection of a combinatorial library of pyrido[2,3-d]pyrimidin-7(8H)-ones (4) has allowed the synthesis of 121 compounds, using known and new synthetic methodologies, and the evaluation of the inhibitory activity against hepatitis C virus (HCV) genotype 1b replicon. Among these compounds, 21{4,10} and 24{2,10} presented very high activities [EC50 = 0.027 μM (CC50 = 5.3 μM) and EC50 = 0.034 μM (CC50 = 13.5 μM), respectively] and high selectivity indexes, 196 and 397. These values are similar to the EC50 reported for sofosbuvir (2) (0.048 μM) using a similar methodological approach and the same virus subtype. 21{4,10} and 24{2,10} are obtained through shorter synthetic itineraries than sofosbuvir and 24{2,10} is achiral contrary to sofosbuvir which presents 4 stereogenic centers. In silico studies suggest that 21{4,10} and 24{2,10} inhibits NS5B polymerase through allosteric site binding.
    Article · Mar 2016 · European Journal of Medicinal Chemistry
  • José Moltó · Fredzzia Graterol · Cristina Miranda · [...] · Bonaventura Clotet
    [Show abstract] [Hide abstract] ABSTRACT: Data on dolutegravir removal by hemodialysis are lacking. To study this, we measured dolutegravir plasma concentrations in samples of blood entering and leaving the dialyzer and resulting dialysate from 5 HIV-infected patients with with end-stage renal disease. Median dolutegravir hemodialysis extraction ratio was 7%. Dolutegravir concentrations after the dialysis session remained far above the protein-binding-adjusted inhibitory concentration. Our results show minimal dolutegravir removal by hemodialysis with no specific dolutegravir dosage adjustments required in this setting.
    Article · Feb 2016 · Antimicrobial Agents and Chemotherapy

Publication Stats

23k Citations


  • 2015
    • IrsiCaixa Institute for AIDS Research
      Badalona, Catalonia, Spain
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2002-2015
    • Hospital Universitari Germans Trias i Pujol
      • Department of Clinical Pharmacology
      Badalona, Catalonia, Spain
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2011-2013
    • TAISS - Técnicas Avanzadas de Investigación en Servicios de Salud
      Madrid, Madrid, Spain
  • 2009
    • University Hospital Donostia
      San Sebastián, Basque Country, Spain
  • 2006-2009
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2008
    • Hospital de la Santa Creu i Sant Pau
      • Santa Creu i Sant Pau Hospital Research Institute
      Barcino, Catalonia, Spain
    • IR-Sant Pau - Sant Pau Institute of Biomedical Research
      Barcino, Catalonia, Spain
    • University College London
      • Department of Primary Care and Population Health (PCPH)
      London, ENG, United Kingdom
  • 2007
    • Fundación Lucha contra el Sida
      Badalona, Catalonia, Spain
  • 2005
    • Deutsche Gesellschaft für Sportmedizin und Prävention e.V.
    • Copenhagen University Hospital Hvidovre
      Hvidovre, Capital Region, Denmark
  • 2004
    • Universitat Rovira i Virgili
      Tarraco, Catalonia, Spain
  • 2000
    • Istituto Superiore di Sanità
      Roma, Latium, Italy