Bonaventura Clotet

Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain

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Publications (757)3686.9 Total impact

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    ABSTRACT: BACKGROUND: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. METHODS: HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. RESULTS: From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). CONCLUSIONS: MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs.
    PLoS ONE 04/2014; 9(4):e94495. · 3.73 Impact Factor
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    ABSTRACT: Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration [FDA] snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with, NCT01449929. Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9-13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p=0·0001). Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. ViiV Healthcare and Shionogi & Co.
    The Lancet 03/2014; · 39.06 Impact Factor
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    ABSTRACT: To characterize a new zinc-finger nuclease (ZFN) that targets close to the sequence of the 32 bp deletion polymorphism in the CCR5 gene, and to generate cells resistant to HIV-1 strains that use CCR5. CCR5Δ32 is a naturally occurring deletion that provides genetic resistance to R5-tropic HIV-1. The specificity and efficacy of a newly identified target for CCR5 gene editing, near the CCR5Δ32 sequence (ZFNCCR5Δ32), was assessed as well as its ability to generate cells resistant to HIV infection with reduced off-target effects. ZFNCCR5Δ32 activity was evaluated by heteroduplex formation in human K562 cells. Assessment of ZFNCCR5Δ32 specificity was analysed in silico. The yield of ZFNCCR5Δ32 in cell culture was improved by fluorescence-activated cell sorting, and the anti-HIV potency of ZFNCCR5Δ32 was measured in vitro in TZM-bl cells against HIV-1 strains. ZFNCCR5Δ32 effectively recognized the CCR5Δ32 region, inducing a frameshift of the CCR5 coding region that resulted in the complete absence of CCR5 expression of mRNA and of protein at the cell surface. CCR5 knockout cells were refractory to HIV-1 infection by the R5-using strain BaL. Unlike previous CCR5 ZFN studies, the new ZFN has no detectable off-target activity. ZFNCCR5Δ32 is a specific and efficient tool for the generation of CCR5 knockouts. Its ability to mimic the natural CCR5Δ32 phenotype in the absence of relevant off-site cutting events suggests that ZFNCCR5Δ32 might be safe in clinical research.
    Journal of Antimicrobial Chemotherapy 03/2014; · 5.34 Impact Factor
  • Proceedings of the National Academy of Sciences 03/2014; · 9.74 Impact Factor
  • Proceedings of the National Academy of Sciences 03/2014; · 9.74 Impact Factor
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    ABSTRACT: The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV-1)-positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV-1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV-coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV-coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous-nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV-1-infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV-coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV-1-positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.
    Journal of Viral Hepatitis 03/2014; · 3.08 Impact Factor
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    ABSTRACT: Background Peptide profiling of biological fluids is a promising tool for biomarker discovery. Blood is an ideal entity for proteomic studies but it is subjected to a proteolytic activity that sets up just at the moment of phlebotomy. Intending to prevent this proteolytic activity, tubes containing protease inhibitors (PI) have been developed.In this study, we evaluated the effect on plasma peptide profile of using tubes containing PI and the evolution of this effect over time.Methods Blood samples from ten subjects were drawn into conventional tubes containing ethylenediaminetetraacetic acid (EDTA) and tubes containing PI. Samples were processed at time “zero” and after 1, 2, 4, and 8 hr. Plasma peptide profiles were analyzed by magnetic bead based technology coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry readout.ResultsWhen comparing plasma peptide profile of blood samples collected into tubes containing PI with samples collected into conventional EDTA tubes, differences in the area of 13 peaks were detected at time “zero”; after 8 hr these differences tended to disappear. Moreover, bradykinin and C3- and C4-derived peptides were produced promptly after blood extraction when samples were collected into conventional EDTA tubes, and the use of PI prevented their generation.Conclusion Considering that time taken to process blood samples affects their peptide profile and a decrease in PI's effect occurs over time, it may be concluded that the use of tubes containing PI for blood collection may be advantageous in the context of research, but may have some limitations regarding clinical practice.
    Journal of Clinical Laboratory Analysis 03/2014; · 1.36 Impact Factor
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    ABSTRACT: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with, number NCT00659789. 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23 100 copies per mL Vacc-4x vs 71 800 copies per mL placebo; p=0·025) and week 52 (median 19 550 copies per mL vs 51 000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.
    The Lancet Infectious Diseases 02/2014; · 19.97 Impact Factor
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    ABSTRACT: There are no clinical trials in which the main objective is to compare the efficacy of efavirenz versus ritonavir-boosted protease inhibitor (PI/r)-based initial antiretroviral therapy (ART) in patients with high plasma HIV-1 RNA levels. This study aims to compare these regimens in this patient population in the setting of routine clinical practice. Multicenter, observational cohort study, including 596 consecutive treatment-naïve patients with plasma HIV-1 RNA >100 000 copies/mL initiating efavirenz or PI/r-based ART between 2000 and 2010. The primary effectiveness endpoint was the percentage of patients with HIV-1 RNA <50 copies/mL at week 48 by intent-to-treat analysis. Among the total, 57% of patients initiated efavirenz and 43% PI/r-regimens (73% lopinavir/r [63%], and fosamprenavir/r, [11%]). HIV-1 RNA suppression to <50 copies/mL at week 48 was higher in the efavirenz group (84% vs 74% [difference 10%, 95% CI 3.4%-16.7%, p=0.002]). The percentage of virologic failures was similar (efavirenz 4% vs PI/r 4%, p=0.686), but voluntary discontinuations and toxicity-related treatment changes were higher with PI/r (4% vs 1%, p=0.006 and 11% vs 6%, p=0.069, respectively). However, resistance selection at failure was higher in patients receiving efavirenz (89% vs 50%; p=0.203). Efavirenz was significantly more effective than lopinavir/r or fosamprenavir/r, whereas no significant differences were observed between efavirenz and darunavir/r or atazanavir/r. The high viral suppression in the efavirenz group was also evident in patients with very high viral loads (>500 000 copies/mL) and in those with low CD4+ cell counts. In routine clinical practice, the effectiveness of initial efavirenz-based regimens was at least similar to or even higher than various PI/r-based regimens in HIV-1 infected patients with plasma HIV-1 RNA >100 000 copies/mL.
    Antiviral therapy 01/2014; · 3.07 Impact Factor
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    ABSTRACT: BACKGROUND:: Latent HIV-1-infected cells generated early in the infection are responsible for viral persistence, and we hypothesized that addition of maraviroc to triple therapy in patients recently infected with HIV-1 could accelerate decay of the viral reservoir.METHODS:: Patients recently infected (<24 weeks) by chemokine receptor 5 (CCR5)-using HIV-1 were randomized to a raltegravir + tenofovir/emtricitabine regimen (control arm, n = 15) or the same regimen intensified with maraviroc (+MVC arm, n = 15). Plasma viral load, cell-associated HIV-1 DNA (total, integrated, and episomal), and activation/inflammation markers were measured longitudinally.RESULTS:: Plasma viral load decayed in both groups, reaching similar residual levels at week 48. Total cell-associated HIV-1 DNA also decreased in both groups during the first month, although subsequently at a slightly faster rate in the +MVC arm. The transient increase in two long terminal repeat (2-LTR) circles observed in both groups early after initiation of treatment decreased earlier in MVC-treated individuals. Early (week 12) increase of CD4 T-cell counts was higher in the +MVC arm. Conversely, CD8 T-cell counts and CD4 T-cell activation decreased slower in the +MVC arm. Absolute CD4 T-cell and CD8 T-cell counts, immune activation, CD4/CD8 T-cell ratio, and soluble inflammation markers were similar in both arms at the end of the study.CONCLUSION:: Addition of maraviroc in early integrase inhibitor-based treatment of HIV-1 infection results in faster reduction of 2-LTR newly infected cells and recovery of CD4 T-cell counts, and a modest reduction in total reservoir size after 48 weeks of treatment. Paradoxically, CCR5 blockade also induced a slower decrease in plasma viremia and immune activation
    AIDS 01/2014; 28:325-34. · 6.41 Impact Factor
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    ABSTRACT: Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking. HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL≤50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile. We included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and -4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction (0-10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily. Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly. NCT01034917.
    PLoS ONE 01/2014; 9(2):e84676. · 3.73 Impact Factor
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    ABSTRACT: BACKGROUND: The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown.METHODS: Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation).RESULTS: Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8(+) T cells were indistinguishable between the two arms and did not change over time between the groups.CONCLUSIONS: Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies
    PLoS ONE 01/2014; 9(1):e87334. · 3.73 Impact Factor
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    ABSTRACT: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. HIV-1 patients newly diagnosed in 27 countries from 2002 through 2007 were included. Inclusion was representative for risk group and geographical distribution in the participating countries in Europe. Trends over time were calculated by logistic regression. From the 4317 patients included, the majority was men-having-sex-with-men -MSM (2084, 48%), followed by heterosexuals (1501, 35%) and injection drug users (IDU) (355, 8%). MSM were more often from Western Europe origin, infected with subtype B virus, and recently infected (<1 year) (p<0.001). The prevalence of TDRM was highest in MSM (prevalence of 11.1%), followed by heterosexuals (6.6%) and IDU (5.1%, p<0.001). TDRM was predominantly ascribed to nucleoside reverse transcriptase inhibitors (NRTI) with a prevalence of 6.6% in MSM, 3.3% in heterosexuals and 2.0% in IDU (p = 0.001). A significant increase in resistance to non- nucleoside reverse transcriptase inhibitors (NNRTIs) and a decrease in resistance to protease inhibitors was observed in MSM (p = 0.008 and p = 0.006, respectively), but not in heterosexual patients (p = 0.68 and p = 0.14, respectively). MSM showed to have significantly higher TDRM prevalence compared to heterosexuals and IDU. The increasing NNRTI resistance in MSM is likely to negatively influence the therapy response of first-line therapy, as most include NNRTI drugs.
    PLoS ONE 01/2014; 9(4):e94495. · 3.73 Impact Factor
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    ABSTRACT: Background: CD4+ count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4+ count have not been assessed in a randomized clinical trial. Methods: Fifty antiretroviral (cART) naïve-HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine during 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, IL-7-receptor/IL-7 system, thymic volume and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Results: Both groups experienced CD4+ count increase that was higher in the EFV group (∆CD4+ 88 vs 315 cells/L LPV/r vs EFV, respectively, p<0.001). Despite this difference in CD4+ gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion and apoptosis on CD4+ and CD8+ T cells (p<0.001 for all), and a significant increase in markers of thymic function, IL-7-receptor and in the levels of central memory CD4+ T cells and naïve subsets of CD8+ T cells (p<0.001 for all) with respect to baseline values was observed without difference between groups. Conclusions: These data support that the differences in CD4+ gain with different cART regimen are not immunologically meaningful and might explain the similar clinical efficacy of these regimens. Key Words: HIV, antiretroviral therapy, immune reconstitution.
    AIDS research and human retroviruses 12/2013; · 2.18 Impact Factor
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    ABSTRACT: The natural history of type-specific oral infection of human papillomavirus (HPV) was assessed in a cohort of HIV-infected men (538 men who have sex with men (MSM); 195 heterosexuals). Risk factors associated with oral HPV infections were examined. The overall prevalence of HPV was 16%: HPV-16 was the most prevalent type (3.7% MSM; 7.8% heterosexuals). The prevalence of HPV-16 in heterosexuals was associated with CD4 nadir counts <200 cells/μL (ORadjusted = 3.0, 95% CI, 1.4-6.3). The overall incidence of HPV was similar between groups (11%), but the incidence of HPV-16 was higher in heterosexuals (ORadjusted = 3.2, 95% CI, 1.1-9.5). Not only MSM but also HIV-infected heterosexual men are at risk of HPV infection. Regular and careful oral inspection is needed.
    Clinical Microbiology and Infection 12/2013; · 4.58 Impact Factor
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    ABSTRACT: There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation. 454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS >= 3.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes. This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough.
    Virology Journal 12/2013; 10(1):350. · 2.09 Impact Factor
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    ABSTRACT: The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients with no or mild-to-moderate fibrosis (stages F0-F2). Liver fibrosis was reassessed by transient elastometry (TE) between January 2009 and November 2011 in HIV/HCV-coinfected patients with stage F0-F2 fibrosis in a liver biopsy performed between January 1997 and December 2007. Patients with liver stiffness at the end of follow-up < 7.1 kPa were defined as nonprogressors, and those with values ≥ 9.5 kPa or who died from liver disease were defined as progressors. Cirrhosis was defined as a cut-off of 14.6 kPa. The follow-up period was the time between liver biopsy and TE. Cox regression models adjusted for age, gender and liver fibrosis stage at baseline were applied. The median follow-up time was 7.8 years [interquartile range (IQR) 5.5-10 years]. The study population comprised 162 patients [115 (71%) nonprogressors and 47 (29%) progressors; 19 patients (11.7%) had cirrhosis]. The median time from the diagnosis of HCV infection to the end of follow-up was 20 years (IQR 16.3-23.1 years). Three progressors died from liver disease (1.8%). The variables associated with a lower risk of progression were age ≤ 38 years (hazard ratio (HR) 0.32; 95% confidence interval (CI) 0.16-0.62; P = 0.001], having received interferon (HR 2.18; 95% CI 1.14-4.15; P = 0.017), being hepatitis B virus surface antigen (HBsAg) negative (HR 0.20; 95% CI 0.04-0.92; P = 0.039), and baseline F0-F1 (HR 0.43; 95% CI 0.28-0.86; P = 0.017). A high proportion of patients with stage F0-F2 fibrosis progress to advanced liver fibrosis. Advanced liver fibrosis must be included in the list of diseases associated with aging. Our results support the recommendation to offer HCV antiviral therapy to HIV/HCV-coinfected patients at early stages of liver fibrosis.
    HIV Medicine 11/2013; · 3.16 Impact Factor
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    ABSTRACT: A relevant fraction of HIV-1-infected individuals (ranging from 15 to 30%) presenting virologically successful highly active antiretroviral therapy fail to recover CD4 T-cell counts. These individuals, called immunodiscordant or immunological nonresponders, are at increased risk of clinical progression and death. Although older age, lower nadir CD4 T-cell count and HCV co-infection are some of clinical predictive factors, immunological mechanisms rely on impaired thymic production and accumulation of apoptosis-prone CD4 T cells. Indeed, immunodiscordant individuals may show increased tissue fibrosis and damage of gut-associated lymphoid tissue that results in higher hyperactivation, inflammation and immunosenescence, altered Treg/Th17 ratio and increased T-cell death. A better knowledge of the final pathogenic mechanism and factors influencing CD4 T-cell recovery will help to select the optimal therapeutic strategies for them.
    Expert Review of Clinical Immunology 11/2013; 9(11):1135-49. · 2.89 Impact Factor

Publication Stats

14k Citations
3,686.90 Total Impact Points


  • 1990–2014
    • Hospital Universitari Germans Trias i Pujol
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine
      Badalona, Catalonia, Spain
  • 2011–2013
    • IrsiCaixa Institute for AIDS Research
      Badalona, Catalonia, Spain
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
    • Sheba Medical Center
      Gan, Tel Aviv, Israel
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2008–2013
    • IGTP Health Sciences Research Institute of the Germans Trias i Pujol Foundation
      Badalona, Catalonia, Spain
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • Corporació Sanitària Parc Taulí
      Catalonia, Spain
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 2003–2013
    • University of California, San Diego
      • Department of Pathology
      San Diego, California, United States
  • 2012
    • IDIBELL Bellvitge Biomedical Research Institute
      Barcino, Catalonia, Spain
    • University of California, Los Angeles
      Los Angeles, California, United States
    • Polytechnic University of Catalonia
      Barcino, Catalonia, Spain
  • 2011–2012
    • TAISS - Técnicas Avanzadas de Investigación en Servicios de Salud
      Madrid, Madrid, Spain
    • Hospital Universitari de Bellvitge
      • Department of Infectious Diseases
      l'Hospitalet de Llobregat, Catalonia, Spain
  • 2008–2012
    • IR-Sant Pau - Sant Pau Institute of Biomedical Research
      Barcino, Catalonia, Spain
    • Universitat Ramon Llull
      • Molecular Engineering Group (GEM)
      Barcino, Catalonia, Spain
  • 2006–2012
    • Fundación Lucha contra el Sida
      Badalona, Catalonia, Spain
    • Howard Hughes Medical Institute
      Maryland, United States
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
    • Chelsea and Westminster Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1990–2012
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
  • 1989–2012
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2007–2011
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
    • Catalan Institution for Research and Advanced Studies
      Barcino, Catalonia, Spain
    • Jewish General Hospital
      Montréal, Quebec, Canada
    • Centre Hospitalier Universitaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2001–2011
    • University College London
      • • Department of Primary Care and Population Health (PCPH)
      • • Department of Infection and Population Health
      London, ENG, United Kingdom
  • 2010
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
    • Fundació Institut Investigació Germans Trias i Pujol
      Badalona, Catalonia, Spain
    • University of New South Wales
      Kensington, New South Wales, Australia
    • IPBS - Institut de Pharmacologie et de Biologie Structurale
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1990–2010
    • Hospital de la Santa Creu i Sant Pau
      Barcino, Catalonia, Spain
  • 2009
    • University Hospital Donostia
      San Sebastián, Basque Country, Spain
    • "la Caixa" Foundation
      Barcino, Catalonia, Spain
    • Generalitat de Catalunya
      Barcino, Catalonia, Spain
    • Atomic Energy and Alternative Energies Commission
      • Pharmacology and Immunoanalysis (SPI)
      Gif-sur-Yvette, Ile-de-France, France
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 1999–2009
    • University of Barcelona
      • • Unitat de Bioestadistica
      • • Department of Medicine
      Barcino, Catalonia, Spain
    • Hospital Universitario Virgen del Rocío
      • Department of Biochemistry
      Hispalis, Andalusia, Spain
  • 2003–2008
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2000–2008
    • KU Leuven
      • • Rega Institute for Medical Research
      • • Department of Biomedical Kinesiology
      Leuven, VLG, Belgium
    • Istituto Superiore di Sanità
      Roma, Latium, Italy
    • University Hospital Vall d'Hebron
      Barcino, Catalonia, Spain
  • 2001–2007
    • University of Copenhagen
      • Department of International Health, Immunology and Microbiology
      København, Capital Region, Denmark
  • 2005
    • Hospital Carlos III - Madrid
      Madrid, Madrid, Spain
    • Cea Leti
      Grenoble, Rhône-Alpes, France
  • 2002
    • Vanderbilt University
      Nashville, Michigan, United States
    • The University of Edinburgh
      • Credit Research Centre
      Edinburgh, Scotland, United Kingdom
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 1999–2002
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
  • 1998
    • Hospital General Universitario Morales Meseguer
      Murcia, Murcia, Spain
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
    • Centre Hospitalier de Luxembourg
      Letzeburg, Luxembourg, Luxembourg
  • 1992
    • Hospital Municipal Badalona
      Badalona, Catalonia, Spain