Bonaventura Clotet

University of Vic, Vic, Catalonia, Spain

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Publications (861)4521.8 Total impact

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    ABSTRACT: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs. To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1. Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4(+) and CD8(+) T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4(+) and CD8(+) T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ(+) CD8(+) T cells being Granzyme B(+) and able to degranulate (CD107a(+)). These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.
    Journal of Translational Medicine 12/2015; 13(1). DOI:10.1186/s12967-015-0392-5 · 3.99 Impact Factor
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    ABSTRACT: HIV-1 specific immune responses induced by a dendritic cells (DCs) therapeutic vaccine might have some effect on viral reservoir. We measured total and integrated HIV-1 DNA in isolated CD4 T cells in patients on cART randomized to receive DC pulsed with autologous HIV-1 (n=24) (DC-HIV-1) or with non-pulsed DCs (n=12) (DC-control) at 6 time-points: before any cART, before STOP1 (first cART interruption 56 weeks before the first immunization to isolate virus for pulsing DCs), before and after vaccinations (VAC1 and VAC2) and at weeks 12 and 48 after second cART interruption. Vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After cART interruption post-vaccination (week 12), while total HIV-1 DNA significantly increased in both arms, integrated HIV-1 DNA did not change in vaccinees (1.8 to 1.9, p=0.22) and increased in controls (1.8 to 2.1, p=0.02) (p=0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in DC-HIV-1 group was transient and at week 48 after cART interruption no differences were observed between groups. HIV-1 specific T cells responses at VAC2 time-point were inversely correlated with total and integrated HIV-1 after cART interruption in vaccinees (r=-0.69, p=0.002 and r=-0.82, p<0.0001, respectively). No correlations were found in controls. HIV-1-specific T-cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. There is an intense interest in developing strategies to target HIV-1 reservoirs that create barriers to cure. The development of therapeutic vaccines aimed at enhancing immune mediated clearance of virus producing cells is of high priority. Few therapeutic vaccine clinical trials have investigate the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell based therapeutic vaccine was able to decrease significantly viral set-point in vaccinated patients with a concomitant increase in HIV-1--specific T cell responses. HIV-1 specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes of viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help to understand how an immunization could shift the virus/host balance and are instrumental to better design strategies to reach the functional cure of HIV-1 infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 06/2015; DOI:10.1128/JVI.01062-15 · 4.65 Impact Factor
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    ABSTRACT: The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique. This was a cross-sectional study. HIV-1-infected adults on first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression. The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age [OR = 0.97 per additional year (95% CI = 0.94-1.00), P = 0.039], ART initiation at WHO stage III/IV [OR = 2.10 (95% CI = 1.23-3.57), P = 0.003] and low ART adherence [OR = 2.69 (95% CI = 1.39-5.19), P = 0.003] were associated with virological failure. Longer time on ART [OR = 1.55 per additional year (95% CI = 1.00-2.43), P = 0.052] and illiteracy [OR = 0.24 (95% CI = 0.07-0.89), P = 0.033] were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects. Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resources. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
    Journal of Antimicrobial Chemotherapy 06/2015; DOI:10.1093/jac/dkv143 · 5.44 Impact Factor
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    The Lancet HIV 05/2015; 2(6). DOI:10.1016/S2352-3018(15)00083-1
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    ABSTRACT: Given the need for easily managed treatment of osteoporosis in HIV-infected patients, we evaluated the efficacy and tolerability of two doses of zoledronate, by comparing three groups of patients: those with annual administration, those with biennial administration (one dose in 2 years) and a control group with no administration of zoledronate. We randomized (2:1) 31 patients on antiretroviral therapy with low bone mineral density (BMD) to zoledronate (5 mg administered intravenously; 21 patients) plus diet counselling and to a control group (diet counselling; 10 patients). At week 48, patients treated with zoledronate were randomized again to receive a second dose (two-dose group; n = 12) or to continue with diet counselling only (single-dose group; n = 9). Changes in lumbar spine and hip BMD and bone turnover markers were compared. The median percentage change from baseline to week 96 in L1-L4 BMD was -1.74% [interquartile range (IQR) -2.56, 3.60%], 7.90% (IQR 4.20, 16.57%) and 5.22% (IQR 2.02, 7.28%) in the control, two-dose and single-dose groups, respectively (P < 0.01, control vs. two doses; P = 0.02, control vs. single dose; P = 0.18, two doses vs. single dose). Hip BMD changed by a median of 2.12% (IQR -0.12, 3.08%), 5.16% (IQR 3.06, 6.74%) and 4.47% (IQR 1, 5.58%), respectively (P = 0.04, control vs. two doses; P = 0.34, two doses vs. single dose). No differences between the two-dose and single-dose groups were detected in bone markers at week 96. The benefits for BMD of a single dose of zoledronate in 2 years may be comparable to those obtained with two doses of the drug after 96 weeks, although this study is insufficiently powered to exclude a real difference. Future studies should explore whether biennial administration of zoledronate is a useful alternative in the treatment of osteoporosis in HIV-infected patients. © 2015 British HIV Association.
    HIV Medicine 05/2015; DOI:10.1111/hiv.12260 · 3.45 Impact Factor
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    ABSTRACT: Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages.
    Cell cycle (Georgetown, Tex.) 04/2015; 14(11). DOI:10.1080/15384101.2015.1030558 · 5.01 Impact Factor
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    ABSTRACT: Although some clinical trials have studied the impact of treatments on bone mineral density (BMD), scarce data are available on protease inhibitor (PI) monotherapies on BMD. The aim of this study was to evaluate changes in BMD in patients after one, two, or three years of a PI monotherapy. This study included 46 HIV-infected patients who switched from a conventional triple antiretroviral strategy to a monotherapy with lopinavir/ritonavir (LPV/r) or darunavir/ritonavir (DRV/r) for one (one-year group, n=16), two (two-year group, n=20), and three (three-year group, n=10) years. BMD was assessed by dual-energy X-ray absorptiometry (DXA). The median percentage of change in total femur BMD was 0.20% after one, 0.79% after two, and -0.31% after three years. The change in lumbar spine was -0.08%, -0.14%, and 0.50% % after the same years. No significant differences were found when patients were classified regarding the type of PI and whether or not had previously received PI or tenofovir. However, patients who interrupted tenofovir or those who started with DRV/r had a higher BMD increment. Patients who had taken non-nucleoside reverse transcriptase inhibitors previously decreased BMD when started PIs. Monotherapy treatment with ritonavir-boosted protease inhibitors (both LPV/r and DRV/r) during one, two, or three years leads to the stabilization of BMD in HIV-infected patients with long-term virological suppression. Larger studies are necessary to compare the effect of starting or withdrawing PIs on BMD.
    The New Microbiologica: official journal of the Italian Society for Medical Virology (SIVIM) 04/2015; 38(2). · 1.60 Impact Factor
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    ABSTRACT: Background. It is unknown if tenofovir disoproxil fumarate (TDF), which is often co-formulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect. Methods. We performed a randomized, cross-over, double-blind, placebo-controlled clinical trial on HIV-1-infected subjects with HIV-1 RNA<50 copies/mL during≥6 months on stable darunavir/ritonavir (800/100 mg QD) or lopinavir/ritonavir (400/100 mg BID) monotherapy, fasting total-cholesterol≥200 or LDL-cholesterol≥130 mg/dL and no lipid-lowering drugs. In Arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (wash-out) and 12 additional weeks of placebo (placebo period). Subjects in Arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (wash-out). The primary endpoints were changes in fasting lipid parameters. (NCT: 01458977). Findings. Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced total-cholesterol from 234 to 205 mg/dL (P<.001), LDL-cholesterol from 155 to 128 mg/dL (P<.001), and HDL-cholesterol from 50.3 to 44.5 mg/dL (P<.001). It also decreased the proportion of subjects with fasting total-cholesterol≥200 mg/dL from 86.7% to 56.8% (P=.001), and LDL-cholesterol≥130 mg/dL from 87.8% to 43.9% (P<.001). After 12-weeks, TDF/FTC exposure was associated with lower total and LDL-cholesterol levels than placebo (P=.001, and P=.002, respectively). Total/HDL-cholesterol ratio and triglyceride levels did not change with TDF/FTC exposure. Conclusions. Co-formulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF.
    Clinical Infectious Diseases 04/2015; DOI:10.1093/cid/civ296 · 9.42 Impact Factor
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    ABSTRACT: Long-term results (>5 years) for synthetic substances used to repair facial lipoatrophy have not been published. We performed a cross-sectional study to evaluate the 10-year safety of polyacrylamide hydrogel (Aquamid®) among the 751 patients from our unit who received facial infiltrations at least 10 years ago. Epidemiological and clinical data such as complications and patient satisfaction were collected. We also identified those patients who presented a facial infection at any time after infiltration. A total of 104 of patients had received Aquamid® at least 10 years ago. Before infiltrations, 24.0%, 41.3% and 34.7% presented very severe, severe and moderate facial lipoatrophy, respectively. After a mean (SD) of 10.3 (0.5) years since the infiltrations, 19.2%, 47.7%, and 31.7% of patients reported moderate, mild, and no signs of facial lipoatrophy. The values reported by physicians for the same categories were 1.9%, 10.6%, and 87.5%. Indurations were detected in 6.7% of patients and nodules in 3.8%. Five patients (4.8%) had a local infection. A further 15 patients with a shorter follow-up (less than 10 years) presented local infections (overall incidence considering the 751 patients who received infiltrations of Aquamid®, 2.7%); the product had to be withdrawn in 3 cases. The majority of patients were highly satisfied (74.8%) or satisfied (23.4%) with the cosmetic results; Among patients with severe or very severe lipoatrophy at baseline, 31.4% were satisfied and 65.7% were highly satisfied. Infiltrations with polyacrylamide hydrogel (Aquamid®) are a safe strategy for the treatment of facial lipoatrophy in the long term. The rate of severe complications was low, and patient satisfaction with the cosmetic results was high. However, facial infections may appear in the long term. Therefore, HIV-infected patients who received synthetic substances should be carefully monitored over time.
    AIDS research and human retroviruses 04/2015; DOI:10.1089/AID.2015.0004 · 2.46 Impact Factor
  • The Lancet HIV 04/2015; 2(4):e127-e136. DOI:10.1016/S2352-3018(15)00027-2
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    ABSTRACT: Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/ CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV- 1 vaccine.
    PLoS ONE 03/2015; 10(3):e0120648. DOI:10.1371/journal.pone.0120648 · 3.53 Impact Factor
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    ABSTRACT: The characterization of host immune responses to HIV in HIV-Controllers and HESN (highly-exposed-seronegative) is needed to guide the development of effective preventive and therapeutic vaccine candidates. However, several technical hurdles severely limit the definition of an effective virus-specific T-cell response. By using a toggle peptide approach that allows to cover HIV sequence diversity and employing a novel, "boosted" cytokine staining flow cytometry strategy, we here describe new T cell response patterns to HIV that would be missed by standard assays. Importantly, this approach also allows detecting broad and strong virus-specific T cell responses in HESN that are characterized by a Th1-cytokine-like effector profile and produce cytokines that have been associated with potential control of HIV infection, including IL-10, IL-13 and IL-22. These results establish a novel approach to improve the current understanding of the HIV-specific T-cell immunity and identify cellular immune responses and individual cytokines as potential markers of relative HIV resistance. As such, the findings also help develop similar strategies for more comprehensive assessments of host immune responses to other human infections and immune-mediated disorders.
    The Journal of Infectious Diseases 03/2015; 211(6):936-946. DOI:10.1093/infdis/jiu534 · 5.78 Impact Factor
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    ABSTRACT: Tenofovir is involved in accelerated bone mineral density (BMD) loss. We recently published a hip BMD improvement at week 48 [+2.1% (95% CI: -0.6, 4.7) (P = 0.043)] in HIV-infected patients with osteopenia/osteoporosis randomized to switch from tenofovir to abacavir (n = 26), although without reaching statistical significance compared with those who maintained tenofovir (n = 28). Here, we present changes at week 48 in bone markers [C-terminal telopeptide of collagen type 1 (CTX), osteocalcin and procollagen type 1 N propeptide (P1NP)] as well as in circulating levels of three proteins involved in bone regulation [osteoprotegerin, receptor activator for NF-κB ligand (RANKL) and sclerostin, a selective regulator of bone formation through the Wnt pathway] in 44 of these patients. χ(2) or Fisher and Student t-tests were performed according to the distribution of the variables. Bone markers decreased only in the abacavir group [mean (SD) CTX changed from 0.543 (0.495) to 0.301 (0.306) ng/mL; mean (SD) osteocalcin changed from 23.72 (22.20) to 13.95 (12.40) ng/mL; and mean (SD) P1NP changed from 54.68 (54.52) to 28.65 (27.48) ng/mL (P < 0.001 in all cases)], reaching statistical significance between the groups at week 48. Osteoprotegerin did not vary, but sclerostin significantly increased in the abacavir group [from 29.53 (27.91) to 35.56 (34.59) pmol/L, P = 0.002]. No significant differences in osteoprotegerin and sclerostin were detected between the groups at week 48. RANKL values were below the limit of detection in all samples. The switch from tenofovir to abacavir seems to induce a positive effect on bone tissue, since bone turnover markers decreased. In addition, circulating sclerostin levels increased, a change associated with improved bone properties. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
    Journal of Antimicrobial Chemotherapy 03/2015; DOI:10.1093/jac/dkv063 · 5.44 Impact Factor
  • Josep M Llibre, Bonaventura Clotet
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    ABSTRACT: The resistance profile of dolutegravir differs significantly from those of earlier integrase inhibitors (INI). Dolutegravir displays in vitro activity against mutant HIV-1 harboring any isolated resistance mutations selected during failures to raltegravir or elvitegravir (Y143C/H/, N155H, Q148H/K/R, E92G/Q, T66A/I/K, T97A, E138A/K, G140A/S). Its activity is only compromised by Q148X mutations combined with other mutations, particularly > 1 mutation. The drug has pharmacokinetic/pharmacodynamic properties (plasmatic t1/2 15.3 h, inhibitory quotient 19, dissociative t1/2 from the IN-DNA complex 71 h) that favor a high genetic barrier to resistance. In vitro the selection of HIV-1 resistance to dolutegravir is extremely difficult to achieve. The mutations eventually selected (R263K, H51Y and E138K) do not confer significant resistance, and induce a fitness cost that prevents HIV-1 from evading drug pressure. Suprisingly, HIV-1 is not able to compensate, leading the virus to a previously unnoticed evolutionary pathway with very low chances of developing resistance to INI or the backbone. No treatment-naïve patients starting dolutegravir therapy (+TDF/FTC o ABC/3TC) have selected resistance in IN or against the backbone. No INI- naïve patients with prior virologic failure selected phenotypic dolutegravir resistance. Only 4 out of 354 patients selected resistance mutations in IN, and rates of selection of mutations in IN or against the backbone were significantly lower than with raltegravir. In multitreated patients with widespread resistance including IN resistance, the high efficacy of dolutegravir was confirmed, irrespective of the previous pattern of IN mutations, provided that Q148X associated with other mutations was absent. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.
    Enfermedades Infecciosas y Microbiología Clínica 03/2015; 33 Suppl 1:20-5. DOI:10.1016/S0213-005X(15)30005-7 · 1.88 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.
    PLoS Medicine 03/2015; 12(3):e1001809. DOI:10.1371/journal.pmed.1001809 · 14.00 Impact Factor
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    ABSTRACT: The safety, immunogenicity, impact on the latent reservoir and rebound of viral load after therapeutic HIV-1 vaccination with recombinant modified vaccinia Ankara-based (MVA-B) HIV-1 vaccine expressing monomeric gp120 and the fused Gag-Pol-Nef polyprotein of clade B with or without a drug to reactivate latent HIV-1 (disulfiram) were assessed. HIV-1-infected patients were randomized to receive three injections of MVA-B (n = 20) or placebo (n = 10). Twelve patients (eight who received vaccine and four who were given placebo) received a fourth dose of MVA-B followed by 3 months of disulfiram. Combined ART (cART) was discontinued 8 weeks after the last dose of MVA-B. Clinical identifier: NCT01571466. MVA-B was safe and well tolerated. A minor, but significant, increase in the T cell responses targeting vaccine inserts of Gag was observed [a median of 290, 403 and 435 spot-forming-cells/10(6) PBMCs at baseline, after two vaccinations and after three vaccinations, respectively; P = 0.02 and P = 0.04]. After interruption of cART, a modest delay in the rebound of the plasma viral load in participants receiving vaccine but not disulfiram was observed compared with placebo recipients (P = 0.01). The dynamics of the viral load rebound did not change in patients receiving MVA-B/disulfiram. No changes in the proviral reservoir were observed after disulfiram treatment. MVA-B vaccination was a safe strategy to increase Gag-specific T cell responses in chronically HIV-1-infected individuals, but it did not have a major impact on the latent reservoir or the rebound of plasma viral load after interruption of cART when given alone or in combination with disulfiram. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
    Journal of Antimicrobial Chemotherapy 02/2015; DOI:10.1093/jac/dkv046 · 5.44 Impact Factor
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    ABSTRACT: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naïve, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens. Randomized, controlled, open-label multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naïve patients with <100 CD4 cells/mm were randomly assigned in a 1:1:1 ratio to efavirenz (n=29), atazanavir/ritonavir (n=30), or lopinavir/ritonavir (n=30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary endpoints were the proportion of patients with HIV-1 RNA <50 copies/mL, adverse events, disease progression, and death. In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells/µL in the efavirenz arm, +197 (146-238) cells/µL in the ritonavir-boosted atazanavir arm, and +205 (178-327) cells/µL in the ritonavir-boosted lopinavir arm (P=0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks (efavirenz, 85.71% [95%CI, 68.5-94.3]; atazanavir, 80% [95%CI, 62.7-90.5]; and lopinavir, 82.8% [95%CI, 65.5-92.4]; p=0.88). Bacterial translocation, inflammation, immune activation, and apoptotic markers-but not D-dimer-declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died. The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen ( registration number: NCT00532168).
    JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2015; 69(2). DOI:10.1097/QAI.0000000000000567 · 4.39 Impact Factor
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    ABSTRACT: Objectives This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data.Methods Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007–2012). Stratum-adjusted (for confounding factors) Mantel–Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived.ResultsBaseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small.Conclusions These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir.
    HIV Medicine 02/2015; DOI:10.1111/hiv.12218 · 3.45 Impact Factor
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    ABSTRACT: We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
    Clinical Microbiology and Infection 01/2015; 21(1):103.e1-6. DOI:10.1016/j.cmi.2014.08.002 · 5.20 Impact Factor

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21k Citations
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  • 2014–2015
    • University of Vic
      Vic, Catalonia, Spain
  • 2010–2015
    • Fundació Institut Investigació Germans Trias i Pujol
      Badalona, Catalonia, Spain
    • University of Liverpool
      Liverpool, England, United Kingdom
    • University of New South Wales
      Kensington, New South Wales, Australia
  • 2007–2015
    • Fundación Lucha contra el Sida
      Badalona, Catalonia, Spain
    • Riga Stradins University
      Rija, Rīga, Latvia
    • Jewish General Hospital
      Montréal, Quebec, Canada
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2004–2015
    • IrsiCaixa Institute for AIDS Research
      Badalona, Catalonia, Spain
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
    • Universitat Rovira i Virgili
      Tarraco, Catalonia, Spain
  • 1989–2015
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
  • 1985–2015
    • Hospital Universitari Germans Trias i Pujol
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine
      • • Department of Clinical Hematology
      Badalona, Catalonia, Spain
  • 2011–2013
    • TAISS - Técnicas Avanzadas de Investigación en Servicios de Salud
      Madrid, Madrid, Spain
    • Sheba Medical Center
      Gan, Tel Aviv, Israel
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2009–2013
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
    • "la Caixa" Foundation
      Barcino, Catalonia, Spain
    • University Hospital Donostia
      San Sebastián, Basque Country, Spain
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 2008–2013
    • IGTP Health Sciences Research Institute of the Germans Trias i Pujol Foundation
      Badalona, Catalonia, Spain
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • Universitat Ramon Llull
      • Molecular Engineering Group (GEM)
      Barcino, Catalonia, Spain
    • IR-Sant Pau - Sant Pau Institute of Biomedical Research
      Barcino, Catalonia, Spain
  • 2002–2013
    • University of California, San Diego
      • Department of Pathology
      San Diego, California, United States
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
    • Utrecht University
      Utrecht, Utrecht, Netherlands
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • The University of Edinburgh
      • Credit Research Centre
      Edinburgh, Scotland, United Kingdom
  • 2012
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 1990–2012
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
  • 2008–2010
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1984–2009
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
  • 2003–2008
    • University College London
      • • Department of Primary Care and Population Health (PCPH)
      • • Department of Infection and Population Health
      London, ENG, United Kingdom
  • 2000–2008
    • Harvard Medical School
      Boston, Massachusetts, United States
    • University Hospital Vall d'Hebron
      Barcino, Catalonia, Spain
    • Istituto Superiore di Sanità
      Roma, Latium, Italy
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 1990–2008
    • Hospital de la Santa Creu i Sant Pau
      • Santa Creu i Sant Pau Hospital Research Institute
      Barcino, Catalonia, Spain
  • 2006
    • Hospital Universitario Ramón y Cajal
      Madrid, Madrid, Spain
    • Chelsea and Westminster Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2005
    • Hospital Carlos III - Madrid
      Madrid, Madrid, Spain
    • Copenhagen University Hospital Hvidovre
      Hvidovre, Capital Region, Denmark
    • Deutsche Gesellschaft für Sportmedizin und Prävention e.V.
    • Institute of Geophysics, China Earthquake Administration
      Peping, Beijing, China
  • 2002–2004
    • Vanderbilt University
      Нашвилл, Michigan, United States
  • 1999–2002
    • Instituto de Salud Carlos III
      • National Center of Microbiology (CNM)
      Madrid, Madrid, Spain
    • Hospital Universitario Virgen del Rocío
      • Department of Biochemistry
      Hispalis, Andalusia, Spain
  • 1998
    • Hospital General Universitario Morales Meseguer
      Murcia, Murcia, Spain
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1996
    • Abbott Laboratories
      North Chicago, Illinois, United States
  • 1992
    • Hospital Municipal Badalona
      Badalona, Catalonia, Spain