Lipids, biomarkers, and subclinical atherosclerosis in treatment-naive HIV patients starting or not starting antiretroviral therapy: Comparison with a healthy control group in a 2-year prospective study.

OBJECTIVE: To assess the effect of HIV infection and combined antiretroviral therapy (c-ART) on various proatherogenic biomarkers and lipids and to investigate their relationship with subclinical atherosclerosis in a cohort of treatment-naive HIV-infected patients. METHODS: We performed a prospective, comparative, multicenter study of 2 groups of treatment-naive HIV-infected patients (group A, CD4>500 cells/µL, not starting c-ART; and group B, CD4<500 cells/µL, starting c-ART at baseline) and a healthy control group. Laboratory analyses and carotid ultrasound were performed at baseline and at months 12 and 24. The parameters measured were low-density lipoprotein (LDL) particle phenotype, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), sCD14, sCD163, monocyte chemoattractant protein-1(MCP-1), and asymmetric dimethylarginine (ADMA). A linear mixed model based on patient clusters was used to assess differences in biomarkers between the study groups and over time. RESULTS: The study population comprised 62 HIV-infected patients (group A, n = 31; group B, n = 31) and 22 controls. Age was 37 (30-43) years, and 81% were men. At baseline, the HIV-infected patients had a worse LDL particle phenotype and higher plasma concentration of sCD14, sCD163, hs-CRP, and LDL-Lp-PLA2 than the controls. At month 12, there was an increase in total cholesterol (p = 0.002), HDL-c (p = 0.003), and Apo A-I (p = 0.049) and a decrease in sCD14 (p = <0.001) and sCD163 (p<0.001), although only in group B. LDL particle size increased in group B at month 24 (p = 0.038). No changes were observed in group A or in the healthy controls. Common carotid intima-media thickness increased in HIV-infected patients at month 24 (Group A p = 0.053; group B p = 0.048). Plasma levels of sCD14, sCD163, and hs-CRP correlated with lipid values. CONCLUSIONS: In treatment-naive HIV-infected patients, initiation of c-ART was associated with an improvement in LDL particle phenotype and inflammatory/immune biomarkers, reaching values similar to those of the controls. HIV infection was associated with progression of carotid intima-media thickness.

Randomized trial of a multidisciplinary lifestyle intervention in HIV-infected patients with moderate-high cardiovascular risk.

OBJECTIVE: To assess the impact of a multidisciplinary lifestyle intervention on cardiovascular risk and carotid intima-media thickness (c-IMT) in HIV-infected patients with Framingham scores (FS) > 10%. DESIGN: Randomized pilot study; follow-up 36 months. METHODS: Virologically suppressed adult HIV-1-infected patients with FS >10% were randomized 1:1 to the intervention group (multidisciplinary lifestyle intervention) or control group (routine care). At baseline and months 12, 24 and 36, lipid parameters were analyzed and carotid ultrasound was performed to determine c-IMT and presence of plaques. Biomarkers were measured at baseline and month 36. The primary endpoints were lipid and FS changes at 36 months. RESULTS: Fifty-four patients were included, 27 in each arm. Median age was 50.5 years, all patients but one were men, and FS was 16.5%. Relative to controls, total and LDL cholesterol had significantly decreased in the intervention group at 24 months (p = 0.039, p = 0.011, respectively). However, no differences between groups were found at month 36 in lipid variables, neither in FS. Tobacco use decreased in the intervention group (p = 0.031). At baseline, 74.5% of patients had subclinical atherosclerosis, and at month 36, we observed a progression in c-IMT that was greater in the intervention group (p = 0.030). D-dimer increased (p = 0.027) and soluble intercellular adhesion molecule-1 decreased (p = 0.018) at 36 months. CONCLUSIONS: In this cohort of HIV-infected patients with FS>10% and a high percentage of subclinical atherosclerosis, a multidisciplinary lifestyle intervention resulted in a slight improvement in some cardiovascular risk factors and the FS during the first 2 years, but did not prevent c-IMT progression.

Prevalence of methicillin-resistant Staphylococcus aureus colonization in HIV-infected patients in Barcelona, Spain: a cross-sectional study.

BACKGROUND: Colonization by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been found to be markedly more common in HIV-infected individuals in the USA. Studies evaluating the prevalence MRSA colonization in HIV-infected populations in Europe are scarce. The aim of this study was to investigate the prevalence of MRSA colonization in a cohort of HIV-infected patients in Barcelona, Spain. METHODS: Nasal and pharyngeal S. aureus carriage was assessed in a random sample of 190 patients from an outpatient HIV clinic. Nasal and pharyngeal swab specimens were obtained for staphylococcal culture from 190 and 110 patients respectively. All MRSA isolates were screened for Panton-Valentine leukocidin (PVL) genes by PCR. Molecular characterization of MRSA isolates was performed by multilocus sequence typing. Data related to HIV infection, healthcare exposure, and previously described risk factors for MRSA were collected from medical records and a questionnaire administered to each patient. RESULTS: The patients' characteristics were as follows: male, 83 %; median (IQR) age, 45 (39-49) years; intravenous drug users, 39 %; men who have sex with men, 32 %; heterosexual, 26 %; CD4 count, 528/µL (IQR 351-740); on antiretroviral therapy, 96 %; and undetectable plasma viral load, 80 %. Sixty-five patients (34 %) were colonized by S. aureus. MRSA colonization was found in 1 % and 2 % of nasal and pharyngeal samples respectively. No PVL positive MRSA strains were detected and all the MRSA isolates belonged to typical hospital-acquired clones. CONCLUSIONS: Our data suggest that CA-MRSA colonization is not currently a problem in HIV-infected individuals in our area.

Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients.

We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m) relative to baseline [93.6 (73.0-109.0)] was seen at weeks 4 [86.5 (34.0-112.0), P = 0.014], 8 [90.0 (49.0-111.0), P = 0.026] and 12 [89.5 (54.0-113.0), P = 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity.

Atherogenic properties of lipoproteins in HIV patients starting atazanavir/ritonavir or darunavir/ritonavir: a substudy of the ATADAR randomized study.

OBJECTIVES: To assess LDL subfraction phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) in naive HIV-infected patients starting atazanavir/ritonavir or darunavir/ritonavir plus tenofovir/emtricitabine. METHODS: This was a substudy of a multicentre randomized study. Standard lipid parameters, LDL subfraction phenotype (by gradient gel electrophoresis) and Lp-PLA2 activity (by 2-thio-PAF) were measured at baseline and weeks 24 and 48. Multivariate regression analysis was performed. Results are expressed as the median (IQR). RESULTS: Eighty-six (atazanavir/ritonavir, n=45; darunavir/ritonavir, n=41) patients were included: age 36 (31-41) years; 89% men; CD4 319 (183-425) cells/mm(3); and Framingham score 1% (0%-2%). No differences in demographics or lipid measurements were found at baseline. At week 48, a mild but significant increase in total cholesterol and HDL-cholesterol was observed in both arms, whereas LDL cholesterol increased only in the darunavir/ritonavir arm and triglycerides only in the atazanavir/ritonavir arm. The apolipoprotein A-I/apolipoprotein B ratio increased only in the atazanavir/ritonavir arm. At week 48, the LDL subfraction phenotype improved in the darunavir/ritonavir arm (increase in LDL particle size and in large LDL particles), whereas it worsened in the atazanavir/ritonavir arm (increase in small and dense LDL particles, shift to a greater prevalence of phenotype B); the worsening was related to the greater increase in triglycerides in the atazanavir/ritonavir arm. No changes in total Lp-PLA2 activity or relative distribution in LDL or HDL particles were found at week 48 in either arm. CONCLUSIONS: In contrast with what occurred in the atazanavir/ritonavir arm, the LDL subfraction phenotype improved with darunavir/ritonavir at week 48. This difference was associated with a lower impact on plasma triglycerides with darunavir/ritonavir.

DRV concentrations and viral load in CSF in patients on DRV/r 600/100 or 800/100mg once daily plus two NRTI.

INTRODUCTION: Darunavir/r (DRV/r) is currently used at a dose of 800/100 mg once daily (OD) in a high proportion of patients. Pharmacokinetic data suggest that 600/100 OD may be effective, reducing toxicity and cost. However, drug concentrations in reservoirs such as cerebrospinal fluid (CSF) might not be adequate to inhibit viral replication. We aimed to evaluate concentrations of DRV and HIV-1 viral load (VL) in CSF patients receiving DRV 600/100 mg OD. METHODS: DRV600 is an ongoing randomized open study comparing DRV/r 800/100 mg (DRV800) vs 600/100 mg (DRV600) OD plus TDF/FTC or ABC/3TC in 100 virologically suppressed patients (eudraCT 2011-006272-39). Here we present the results of a CSF sub-study. A lumbar puncture (LP) was performed in participating patients after at least six months of inclusion in the study, 20-28 hours after a dose of DRV/r. VL (PCR, LOD 40 copies/mL) was determined in CSF and in plasma. DRV concentrations were quantified in CSF by liquid chromatography mass spectrometry (LC/MS/MS) and in plasma using high-performance liquid chromatography (HPLC). RESULTS: Sixteen patients were included (eight in each arm). All DRV600 patients and four out of eight DRV800 patients received TDF/FTC, and the other four ABC/3TC. 75% were males, median (range) age was 48 (17-71) years, CD4 cell count 532 cells/mL (190-1,394). Median total time on DRV/r was 30 (11-57) months, and since the beginning of the study 8 (6-12) months in DRV800 and 10 (7-12) months in DRV600 patients. LP was performed a median of 26 (24-28) hours after the last DRV/r+TVD or KVX dose. In DRV600 patients the median DRV plasma levels were 1,674 (326-3,742) ng/mL, CSF levels 17.08 (5.79-30.19) ng/mL and DRV CSF:plasma ratio 0.0084 (0.0028-0.0388), while in the DRV800 arm, median DRV plasma levels were 1,707 (958-3,910) ng/mL, CSF levels 13.23 (3.47-32.98) ng/mL and DRV CSF:plasma ratio 0.0104 (0.0018-0.0262). All patients had VL<40 copies/mL in plasma and 14 patients VL<40 copies/mL in CSF. Two patients (1 in each arm, and taking TDF/FTC) had detectable VL in CSF (280 and 159 c/mL). These patients had the lowest CSF DRV concentrations (5.47 and 3.47 ng/mL), with plasma DRV concentrations of 802 and 958 ng/mL respectively. CONCLUSIONS: CSF DRV concentrations and CSF VL were similar between patients receiving DRV/r 800/100 mg or 600/100 mg OD. Low CSF DRV concentrations might be associated with viral escape in CNS. This may be taken into account in patients receiving OD DRV/r. Larger studies should confirm these findings.

[Resistance profile of rilpivirine]. / Perfil de resistencia de rilpivirina.

Rilpivirine (RPV) is a new second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) approved for use in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) as initial therapy in treatment-naïve HIV-1-infected patients with a baseline viral load ≤100,000 copies/mL. RPV is a diarylpyrimidine derivative with potent in vitro activity against multiple HIV-1 variants with resistance mutations to first-generation NNRTI such as K103N. In vitro studies and phase III clinical trials have allowed the identification of 16 mutations associated with resistance to RPV K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L. The risk of virologic failure in patients receiving RPV plus 2 NRTI with plasma viral load ≤ 100,000 copies/mL is low, but a high percentage of patients failing RPV develop resistance mutations to both RPV and NRTI. The most common resistance mutation that emerges in this setting is E138K. This mutation is usually associated with M184I due to a double compensatory effect of this combination, which confers resistance to RPV, as well as to lamivudine and emtricitabine. The emergence of RPV resistance confers cross-resistance to all NNRTI and, importantly, high percentages of cross-resistance to etravirine.

Community-acquired Legionella pneumophila pneumonia: a single-center experience with 214 hospitalized sporadic cases over 15 years.

Legionella pneumophila has been increasingly recognized as a cause of community-acquired pneumonia (CAP) and an important public health problem worldwide. We conducted the present study to assess trends in epidemiology, diagnosis, clinical features, treatment, and outcomes of sporadic community-acquired L. pneumophila pneumonia requiring hospitalization at a university hospital over a 15-year period (1995-2010). Among 3934 nonimmunosuppressed hospitalized patients with CAP, 214 (5.4%) had L. pneumophila pneumonia (16 cases were categorized as travel-associated pneumonia, and 21 were part of small clusters). Since the introduction of the urinary antigen test, the diagnosis of L. pneumophila using this method remained stable over the years (p = 0.42); however, diagnosis by means of seroconversion and culture decreased (p < 0.001 and p = 0.001, respectively). The median age of patients with L. pneumophila pneumonia was 58.2 years (SD 13.8), and 76.4% were male. At least 1 comorbid condition was present in 119 (55.6%) patients with L. pneumophila pneumonia, mainly chronic heart disease, diabetes mellitus, and chronic pulmonary disease. The frequency of older patients (aged >65 yr) and comorbidities among patients with L. pneumophila pneumonia increased over the years (p = 0.06 and p = 0.02, respectively). In addition, 100 (46.9%) patients were classified into high-risk classes according to the Pneumonia Severity Index (groups IV-V). Twenty-four (11.2%) patients with L. pneumophila pneumonia received inappropriate empirical antibiotic therapy at hospital admission. Compared with patients who received appropriate empirical antibiotic, patients who received inappropriate therapy more frequently had acute onset of illness (p = 0.004), pleuritic chest pain (p = 0.03), and pleural effusion (p = 0.05). The number of patients who received macrolides decreased over the study period (p < 0.001), whereas the number of patients who received levofloxacin increased (p < 0.001). No significant difference was found in the outcomes between patients who received erythromycin and clarithromycin. However, compared with macrolide use during hospital admission, levofloxacin therapy was associated with a trend toward a shorter time to reach clinical stability (median, 3 vs. 5 d; p = 0.09) and a shorter length of hospital stay (median, 7 vs. 10 d; p < 0.001). Regarding outcomes, 38 (17.8%) patients required intensive care unit (ICU) admission, and the inhospital case-fatality rate was 6.1% (13 of 214 patients). The frequency of ICU admission (p = 0.34) and the need for mechanical ventilation (p = 0.57) remained stable over the study period, but the inhospital case-fatality rate decreased (p = 0.04). In the logistic regression analysis, independent factors associated with severe disease (ICU admission and death) were current/former smoker (odds ratio [OR], 2.96; 95% confidence interval [CI], 1.01-8.62), macrolide use (OR, 2.40; 95% CI, 1.03-5.56), initial inappropriate therapy (OR, 2.97; 95% CI, 1.01-8.74), and high-risk Pneumonia Severity Index classes (OR, 9.1; 95% CI, 3.52-23.4). In conclusion, L. pneumophila is a relatively frequent causative pathogen among hospitalized patients with CAP and is associated with high morbidity. The annual number of L. pneumophila cases remained stable over the study period. In recent years, there have been significant changes in diagnosis and treatment, and the inhospital case-fatality rate of L. pneumophila pneumonia has decreased.

Clinical features, etiology, and outcomes of community-acquired pneumonia in patients with diabetes mellitus.

We performed an observational analysis of a prospective cohort of immunocompetent hospitalized adults with community-acquired pneumonia (CAP) to determine the epidemiology, clinical features, and outcomes of pneumonia in patients with diabetes mellitus (DM). We also analyzed the risk factors for mortality and the impact of statins and other cardiovascular drugs on outcomes. Of 2407 CAP episodes, 516 (21.4%) occurred in patients with DM; 483 (97%) had type 2 diabetes, 197 (40%) were on insulin treatment, and 119 (23.9%) had end-organ damage related to DM. Patients with DM had different clinical features compared to the other patients. They were less likely to have acute onset, cough, purulent sputum, and pleural chest pain. No differences in etiology were found between study groups. Patients with DM had more inhospital acute metabolic complications, although the case-fatality rate was similar between the groups. Independent risk factors for mortality in patients with DM were advanced age, bacteremia, septic shock, and gram-negative pneumonia. Patients with end-organ damage related to DM had more inhospital cardiac events and a higher early case-fatality rate than did the overall population. The use of statins and other cardiovascular drugs was not associated with better CAP outcomes in patients with DM. In conclusion, CAP in patients with DM presents different clinical features compared to the features of patients without DM.

[Hyponatremia in elderly patients admitted in an acute geriatric care unit. prevalence and prognosis]. / Hiponatremia en pacientes ancianos ingresados en una Unidad de Agudos de Geriatría. Prevalencia y pronóstico.

BACKGROUND AND OBJECTIVE: In order to analyze the prevalence of hyponatremia in in-hospital elderly patients and its prognosis factor value, we performed a transversal prospective study in an Acute Geriatric Unit (AGU). PATIENTS AND METHODS: Two hundred and sixty in-hospital patients were collected prospectively in an AGU. Sociodemographic and lab data were collected as well as the Barthel, Pfeiffer and Charlson tests. A questionnaire was performed in hospital. Hyponatremia was considered when the plasmatic sodium was ≤134 mmol/l. RESULTS: The sample consisted of 137 women (52.7%) and 123 men (47.3%). Mean age was 83.6 years (SD 7.9). Mean plasmatic sodium values were 137.3 mmol/l (range 112-168). Emergency lab tests showed 60 patients with hyponatremia (23.7%), 35 (13.6%) in the AGU. Cardiopulmonary were the most related diseases. Mean hospital length of stay was 12.8 days (SD 12.8). In-hospital mortality was 12.9%. We observed a statistic relationship between the presence of hyponatremia and a greater mean length of stay (15.53 vs 11.99 days, P=.003). No relationship was found between hyponatremia and mortality (15 vs 12.7%, P=.588). CONCLUSION: Hyponatremia in patients admitted in an AGU is a prevalent disorder related with a greater hospital length of stay, but not with mortality.