[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess changes in antibiotic resistance, epidemiology, and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our center from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/d) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4-6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR: gentamicin MIC ≥512 mg/L, streptomycin MIC ≥1024 mg/L or both) were observed in recent years (24% in 1997-2006 and 49% in 2007-2011; P=0.03). The use of A+C increased over time: 1997-2001, 4/18 (22%); 2002-2006, 5/16 (31%); and 2007-2011, 30/35 (86%) (P<0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (P=0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only 1 patient (3%) treated with A+C had to discontinue treatment (P<0.001). Only development of heart failure and previous chronic renal failure were independently associated with one-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR 0.7, 95%CI 0.2-2.2, P=0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results.This article is protected by copyright. All rights reserved.
Clinical Microbiology and Infection 07/2014; · 4.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Highly active antiretroviral therapy has helped to improved control of the HIV infection, and has led to a progressively older population with the infection having a life expectancy quite similar to that of the general population. On the other hand, it is also known that HIV infection, even in patients with undetectable viral loads and good immunity, carries an increased cardiovascular risk, as well as an increased incidence of certain cancers. Therefore, the majority of HIV-infected patients receive several drugs (either prescribed by the physician or self-administered) combined with antiretrovirals. This article reviews the interactions between antiretrovirals and other drugs that can cause significant damage to patients, or even be life-threatening and of whom clinicians, especially those not directly treating HIV-infected patients, should be aware. A review is also presented on the implications of interactions between antiretrovirals and other drugs in special situations, such as the co-administration with cytostatics, immunesuppressants used in solid organ transplantation, or patients receiving new treatments for hepatitisC. Generally, combinations with two nucleos(t)ide reverse transcriptase inhibitors and raltegravir (or in the near future, dolutegravir) are those with less potential for clinically significant interactions.
Enfermedades Infecciosas y Microbiología Clínica 06/2014; · 1.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We tested if an increase of immune activation and drop of CD4+ T cells induced by different antigenic stimuli could be associated with changes in thymic function and IL-7/CD127 system.
Twenty-six HIV-infected patients under cART were randomized to receive during 12 months a complete immunization schedule (7 vaccines and 15 doses) or placebo. Thereafter, cART was interrupted 6 months. Changes in the thymic function and IL-7/CD127 system after 3 different antigenic stimuli (vaccines, episodes of low level intermittent viremia before cART interruption or viral load rebound after cART interruption) were assessed.
During the period on cART neither vaccines nor low level viremia influenced thymic function or IL-7/CD127 system parameters. Analyzing the cohort as a whole while on cART, a significant improvement was observed in thymic function as measured by an increase in the thymic volume (p=0.024), TRECs-bearing cells (p=0.012) and naive CD4+ and CD8+ T cells (p=0.069 both). No significant changes were observed in the IL-7/CD127 system. After cART interruption, a decrease of TRECs (p<0.001) and naïve CD8+ T cells (p<0.001), an increase of IL-7 and expression of CD127 on naïve and memory CD4+ T cells (p=0.028, p=0.088 and p=0.04, respectively) and a significant decrease of CD127 on naive and memory CD8+ T cells (p=0.01, p=0.006, respectively) were observed.
Low level transient antigenic stimuli during cART were not associated with changes on thymic function or IL-7/CD127 system. Conversely, viral load rebound very early after cART interruption influenced thymic function and IL-7/CD127 system.ClinicalTrials.gov number NCT00329251.
[Show abstract][Hide abstract] ABSTRACT: Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy.
The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age ≥18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100 000 vs ≥100 000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than -12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444.
Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI -2·2 to 11·8; p=0·171). Patients with baseline viral load of at least 100 000 copies per mL showed similar results (87·2% vs 77·9%, respectively; difference 9·3%, 95% CI -2·8 to 21·5; p=0·145). Toxicity-related or tolerability-related discontinuations were more common in the triple-therapy group (n=10 [4·9%]) than in the dual-therapy group (n=1 [0·4%]; difference 4·5%, 95% CI -8·1 to -0·9; p=0·011). 65 adverse events in the dual-therapy group and 88 in the triple-therapy group were possibly or probably drug related (p=0·007). Two serious adverse events occurred, both in the dual-therapy arm, one of which (a case of gastritis) was reported as possibly or probably related to drug treatment.
Dual therapy with lopinavir and ritonavir plus lamivudine regimen warrants further clinical research and consideration as a potential therapeutic option for antiretroviral-therapy-naive patients.
Fundación Huésped and AbbVie.
The Lancet Infectious Diseases 04/2014; · 19.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus (MRSA) bacteremia, and recent data point to a similar effect on MSSA bacteremia. We aimed to evaluate the effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin. Methods. We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (< 1.5 µg/mL) and high vancomycin MIC (≥ 1.5 µg/mL). The primary endpoint was in-hospital mortality. Results. We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC<1.5 µg/mL and 40 (43%) a vancomycin MIC≥1.5 µg/mL. In-hospital mortality was 30% (16/53) in patients with a low vancomycin MIC and 53% (21/40) in those with a high vancomycin MIC (p=0.030). No correlation was found between oxacillin MIC and vancomycin or daptomycin MIC. Logistic regression analysis showed that higher vancomycin MIC increased in-hospital mortality 3-fold (OR 3.1, 95% CI 1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and non-septic complicated endocarditis. Conclusion. Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of antibiotics.
[Show abstract][Hide abstract] ABSTRACT: To determine the relationship between measures of renal function [current estimated glomerular filtration rate (eGFR) and proportion of follow-up with a low eGFR (%FU ≤60 ml/min)] and fatal/ nonfatal AIDS, non-AIDS events and all-cause mortality.
AIDS (London, England) 03/2014; 28(5):727-737. · 4.91 Impact Factor
[Show abstract][Hide abstract] 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. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Highly active antiretroviral therapy has helped to improved control of the HIV infection, and has led to a progressively older population with the infection having a life expectancy quite similar to that of the general population. On the other hand, it is also known that HIV infection, even in patients with undetectable viral loads and good immunity, carries an increased cardiovascular risk, as well as an increased incidence of certain cancers. Therefore, the majority of HIV-infected patients receive several drugs (either prescribed by the physician or self-administered) combined with antiretrovirals. This article reviews the interactions between antiretrovirals and other drugs that can cause significant damage to patients, or even be life-threatening and of whom clinicians, especially those not directly treating HIV-infected patients, should be aware. A review is also presented on the implications of interactions between antiretrovirals and other drugs in special situations, such as the co-administration with cytostatics, immunesuppressants used in solid organ transplantation, or patients receiving new treatments for hepatitis C. Generally, combinations with two nucleos(t)ide reverse transcriptase inhibitors and raltegravir (or in the near future, dolutegravir) are those with less potential for clinically significant interactions.
Enfermedades Infecciosas y Microbiología Clínica 01/2014; · 1.48 Impact Factor
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] ABSTRACT: Clinical use of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) may be hampered by toxicity, interactions or resistance issues. Simple and effective antiretroviral regimens avoiding both drug classes may be needed for selected patients.
This was a prospective cohort study. Virologically suppressed patients on PI or NRTI regimens, with problems of tolerability, safety concerns due to comorbidities or risk of drug interactions for both PIs and NRTIs, were given the opportunity to switch their regimen to etravirine plus raltegravir. Patients were required not to have prior virological failure to raltegravir and if there was prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure, only patients in whom efficacy of etravirine could be anticipated through the Stanford Drug Resistance Database were included. Follow-up was scheduled for at least 48 weeks, unless the patient was lost to follow-up or discontinued therapy.
Twenty-five patients were included. Their median age was 54 years; they had a median of 16 years on antiretroviral therapy and a median of nine previous regimens; 21 (84%) patients had previous virological failure; and 15 (60%) patients had a genotypic test that showed three or more NRTI mutations in 9 (36%), four or more PI mutations in 11 (44%) and at least one NNRTI mutation in 8 (32%) patients. At 48 weeks efficacy was 84% (95% CI 65.3%-93.6%) by intent-to-treat analysis and 91.3% (95% CI 73.2%-97.6%) by per-protocol analysis. One (4%) patient died, two (8%) discontinued due to intolerance and one (4%) experienced virological failure. The CD4/CD8 ratio and plasma lipids improved.
Dual therapy with etravirine plus raltegravir was well tolerated and maintained durable viral suppression in selected virologically suppressed patients for whom both PI and NRTI therapy was challenging.
Journal of Antimicrobial Chemotherapy 10/2013; · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Little is known about the stability of HIV-1 cross-neutralizing responses. Taking into account that neutralization breadth has been positively associated to plasma viral load, there is no explanation for the presence of broadly neutralizing responses in a group of patients on treatment with undetectable viremia. In addition, the B-cell profile responsible for broadly cross-neutralizing responses is unknown. Here we study the evolution of neutralizing responses and the B-cell subpopulation distribution in a group of patients with broadly cross-reactive HIV-1 neutralizing activity. We studied neutralization breadth evolution in a group of six previously identified broadly cross-neutralizers and six control patients during a 6-year period with a previously described minipanel of recombinant viruses from five different subtypes. B-cell subpopulation distribution during the study was also determined by multiparametric flow-cytometry. Broadly cross-neutralizing activity was transient in four broadly cross-neutralizers and stable, up to 4.6 years, in the other two. In four out of five broadly cross-neutralizers who initiated treatment, a neutralization breadth loss occurred after viremia had been suppressed for as much as 4 to 20 months. B-cell subpopulation analyses revealed a significant increase in the frequency of naïve B cells in broadly cross-reactive samples, compared with samples with less neutralization breadth (increased from 44% to 62%). We also observed a significant decrease in tissue-like and activated memory B cells (decreased from 19% to 12% and from 17% to 9% respectively). Our data suggest that HIV-1 broadly cross-neutralizing activity is variable over time and associated with detectable viremia and partial B-cell restoration.
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells have a central role in HIV infection. On one hand, they are essential to induce strong HIV-specific CD4+ helper T-cell responses that are crucial to achieve a sustained and effective HIV-specific CD8+ cytotoxic T-lymphocyte able to control HIV replication. On the other hand, DCs contribute to virus dissemination and HIV itself could avoid a correct antigen presentation. As the efficacy of immune therapy and therapeutic vaccines against HIV infection has been modest in the best of cases, it has been hypothesized that ex vivo generated DC therapeutic vaccines aimed to induce effective specific HIV immune responses might overcome some of these problems. In fact, DC-based vaccine clinical trials have yielded the best results in this field. However, despite these encouraging results, functional cure has not been reached with this strategy in any patient. In this Commentary, we discuss new approaches to improve the efficacy and feasibility of this type of therapeutic vaccine.
Human vaccines & immunotherapeutics. 08/2013; 9(11).
[Show abstract][Hide abstract] ABSTRACT: Combinations of new classes of antiretroviral drugs are attractive options to avoid toxicity associated with nucleoside reverse transcriptase inhibitors (NRTIs) and to provide a full active regimen in patients with some degree of resistance to NRTIs. However, data on the pharmacokinetic (PK) profiles of these regimens are limited. We explore the plasma PK profile of raltegravir (RAL) at a dose of 400 mg twice a day plus darunavir/ritonavir (DRV/RTV) at a dose of 800/100 mg once a day in HIV-1-infected patients.
This was a pilot, open-label, fixed-sequence, prospective, single-center single-arm PK study. The treating physician chose an NRTI-sparing regimen because of toxicity or resistance mutations to NRTIs, which included DRV/RTV 800/100 mg once daily plus RAL 400 mg twice daily. All patients were RAL and DRV naive and had no evidence of protease inhibitor mutations. After at least 15 days on therapy, patients were admitted for a 24-hour PK study. Laboratory tests to assess efficacy and safety were performed at all study visits.
Fifteen patients were included. The geometric mean values for DRV were AUC0-24 68,730 ng·h·mL [95% confidence interval (CI): 58,970-86,480], Ctrough 1330 ng/mL (95% CI: 1110-1760; IC-50 for wild-type and resistant HIV-1 strains was 55 and 550 ng/mL, respectively), Cmax 7630 ng/mL (95% CI: 6740-9000), and t1/2 10.9 hours (95% CI: 9.20-13.99). Geometric mean values for RAL were AUC0-12 3050 ng·h·mL (95% CI: 2530-5180); Ctrough 40 ng/mL (95% CI: 30-80), Cmax 970 ng/mL (95% CI: 840-2270), t1/2 2.68 hours (95% CI: 1.97-4.40). No adverse effects including rash or laboratory test abnormalities were noted. At week 24, the HIV-1 viral load was below 37 copies/mL in all patients.
Our data suggest that dual therapy with RAL 400 mg twice daily plus DRV/RTV 800/100 mg once daily had a favorable PK profile for both drugs and that short-term efficacy and tolerability of this combination were adequate.
Therapeutic drug monitoring 07/2013; · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Two randomised, placebo-controlled trials—BENCHMRK-1 and BENCHMRK-2—investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study).
Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240.
1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2.
Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options.
Merck Sharp & Dohme.
The Lancet Infectious Diseases 07/2013; 13(7):587–596. · 19.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally, further research involving the generalized epidemic is needed to determine when suboptimal drug use may occur and when regular testing and monitoring of the long-term consequences of ART use may not be routine.
The Journal of Infectious Diseases 06/2013; 207 Suppl 2:S101-6. · 5.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. HIV-positive persons have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods. In the general population, 23 common single nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on gender and cohort. Results. A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P=2.9x10-4). In the final, multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval, 1.05-2.04). This effect was similar to hypertension (OR=1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR=1.51; 95% CI, 1.16-1.96), diabetes (OR=1.66; 95% CI, 1.10-2.49), >1 year lopinavir exposure (OR=1.36; 95% CI, 1.06-1.73) and current abacavir treatment (OR=1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of non-genetic CAD risk factors, and did not change after adjustment for family history. Conclusions. In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.
[Show abstract][Hide abstract] ABSTRACT: Background: The reduction of risk of non-AIDS events after antiretroviral therapy (cART) initiation and the crude incidence rate (CIR) of these events in patients who control the viral load without cART (controllers) in a cohort of 574 antiretroviral naïve patients with a baseline CD4 T cell count above 500 cells/mm3 were assessed. Methods: Non-AIDS severe events were defined as a first admission to the hospital due to non-AIDS-defining malignancies, cardiovascular, neuropsychiatric, liver-related or end-stage renal disease events. Potential determinants of non-AIDS/death events were studied using Cox regression models. Results: Eighty-five non-AIDS/death events occurred during 6062 persons-years of follow-up with a CIR of 1.4 per-100-PYFU. Factors associated with non-AIDS/death event were age (HR 3.4; 95%CI:1.6-6.9), nadir CD4 below 350 cells/mm3 (HR 2.5; 95%CI:1.4-4.6) and a last determination of viral load above the median (HR 1.9; 95%CI:1.0-3.3). The CIR of non-AIDS/death events was 2.1 and 1.8 per-100-PYFU before and after cART in patients who started cART (n=446). A reduction of CIR of non-AIDS events after cART initiation was only observed in patients with a nadir of CD4 above 350 cells/mm3 (2.5 vs 0.6 per-100-PYFU P= 0.004 and remained stable after cART in patients with a median nadir of CD4 below 350 cells/mm3. CIR was similar in elite, viremic and non controllers (1.1, 1.0 and 1.5 per-100-PYFU, respectively, P=0.25). Conclusions: Reduction of CIR of non-AIDS events after cART initiation depends on nadir CD4 T cell count. Most of the controllers patients had a CIR similar to non-controllers. These data support the early initiation of cART in HIV infected patients.
AIDS research and human retroviruses 03/2013; · 2.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Development of high-level daptomycin resistance (HLDR; MIC ≥256 mg/L) after exposure to daptomycin has recently been reported in viridans-group streptococci (VGS) isolates. Our study objectives were as follows: to know whether in vitro development of HLDR after exposure to daptomycin was common among clinical isolates of VGS and Streptococcus bovis; to determine whether HLDR also developed during administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible penicillin-resistant Streptococcus mitis strain S. mitis-351; and to establish whether combination with gentamicin prevented development of HLDR in vitro and in vivo. In vitro studies were performed in 114 VGS strains (Mitis group, 92; Anginosus group, 10; Mutans group, 8; Salivarius group, 4) and 54 S. bovis strains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 hours of exposure to daptomycin in 27% of the Mitis group: S. mitis (27%), S. oralis (47%), and S. sanguis (13%). In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 hours of daptomycin administered at 6 mg/kg/24 h and 10 mg/kg/24 h, respectively. In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal against S. mitis-351 at concentrations tested of 0.5, and 1 times the MIC and prevented the development of HLDR. In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as that of vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequently in vitro and in vivo among Mitis-group streptococci. Combination with gentamicin enhanced the activity of daptomycin and prevented development of HLDR in most cases.
Antimicrobial Agents and Chemotherapy 03/2013; · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The potential for implementation of HIV vaccine trials in hard-to-reach female sex workers in an inner city area of Barcelona, Spain was assessed via a study of HIV risk, willingness to participate and the success of retention strategies. In 130 women, serological HIV status, behavioral risk exposures and willingness to participate in future HIV vaccine trials were recorded every six months using a confidential questionnaire. An enhanced retention (ER) strategy was compared with a control retention (CR) strategy comprising the recording of data on appointment cards. HIV seroincidence and retention rates were estimated. Retention rates after 6 and 12 mo of follow-up in the ER group were 76% and 69% respectively compared with 16% and 13% in the CR group. Among the ER group 97% were willing to participate in HIV vaccine trials at baseline and, after 12 mo of follow-up. Willingness was significantly associated with higher HIV risk exposure, and higher education level. Successfully retaining these cohorts over time in settings with a high HIV seroincidence rate is an ongoing challenge that will need to be addressed to ensure participation in future trials. Furthermore, as we have demonstrated, the fact that retaining hard-to-reach populations is difficult should not exclude this target population for HIV vaccine and prevention trials.
Human vaccines & immunotherapeutics. 01/2013; 9(2).